Reevaluation of sodium thiosulfate otoprotection using the consensus International Society of Paediatric Oncology Ototoxicity Scale: A report from the Children's Oncology Group study ACCL0431.

In two randomized trials (Children's Oncology Group ACCL0431 and International Childhood Liver Tumour Strategy Group SIOPEL-6), sodium thiosulfate (STS) demonstrated efficacy in preventing cisplatin-induced hearing loss (CIHL). However, the measures used in those trials have been superseded by the consensus International Society of Paediatric Oncology (SIOP) Ototoxicity Scale. To provide benchmark data for STS efficacy when using this contemporary scale, we reanalyzed ACCL0431 hearing outcomes with the SIOP scale and using multiple timepoints. Compared to the control arm, STS significantly reduced CIHL when assessed by the SIOP scale across these different approaches. These results provide critical data to inform treatment discussions and support future potential trial designs comparing otoprotectants.

Prospective Evaluation of the Fungitell® (1→3) Beta-D-Glucan Assay as a Diagnostic Tool for Invasive Fungal Disease in Pediatric Allogeneic Hematopoietic Cell Transplantation: A Report from the Children's Oncology Group.

BACKGROUND: Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non-invasive biomarkers, such as the beta-D-glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta-D-glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post-HCT period. METHODS: Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post-HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at the manufacturer cutoff of 80 pg/ml. IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the Fungitell® BDG assay for the outcome of proven or probable IFD. RESULTS: A total of 51 patients (out of 290 patients in the parent trial) contributed blood specimens. In total, 278 specimens were evaluated. Specificity was 80.8% (95% confidence interval [CI]: 75.6%-85.3%), and NPV was over 99% (95% CI: 86.8%-99.9%). However, there were no true positive results, resulting in sensitivity of 0% (95% CI: 0.0%-84.2%) and PPV of 0% (95% CI: 0.0%-6.7%). CONCLUSIONS: Fungitell® BDG screening is of limited utility in diagnosing IFD in the post-HCT period, mainly due to high false-positive rates. Fungitell® BDG surveillance testing should not be performed in children during the early post-HCT period while receiving antifungal prophylaxis as the pretest probability for IFD is low.

Prospective Evaluation of Galactomannan and (1→3) ß-d-Glucan Assays as Diagnostic Tools for Invasive Fungal Disease in Children, Adolescents, and Young Adults With Acute Myeloid Leukemia Receiving Fungal Prophylaxis.

BACKGROUND: Patients receiving chemotherapy for acute myeloid leukemia (AML) are at high risk for invasive fungal disease (IFD). Diagnosis of IFD is challenging, leading to interest in fungal biomarkers. The objective was to define the utility of surveillance testing with Platelia Aspergillus galactomannan (GM) enzyme immunoassay (EIA) and Fungitell ß-d-glucan (BDG) assay in children with AML receiving antifungal prophylaxis. METHODS: Twice-weekly surveillance blood testing with GM EIA and BDG assay was performed during periods of neutropenia in the context of a randomized trial of children, adolescents, and young adults with AML allocated to fluconazole or caspofungin prophylaxis. Proven or probable IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for Platelia and Fungitell assays alone and in combination for the outcomes of proven and probable invasive aspergillosis (IA) or invasive candidiasis (IC). RESULTS: Among 471 patients enrolled, 425 participants (209 fluconazole and 216 caspofungin) contributed ≥1 blood specimen. In total, 6103 specimens were evaluated, with a median of 15 specimens per patient (range 1-43). The NPV was >99% for GM EIA and BDG assay alone and in combination. However, there were no true positive results, resulting in sensitivity and PPV for each assay of 0%. CONCLUSIONS: The GM EIA and the BDG assay alone or in combination were not successful at detecting IA or IC during periods of neutropenia in children, adolescents, and young adults with AML receiving antifungal prophylaxis. Utilization of these assays for surveillance in this clinical setting should be discouraged.

Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial.

BACKGROUND: Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients receiving temozolomide (TMZ) and irinotecan with that of patients receiving TMZ, irinotecan, and bevacizumab for recurrent MB/central nervous system (CNS) primitive neuroectodermal tumor (PNET). METHODS: Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m2 /day PO on days 1-5) and irinotecan (50 mg/m2 /day IV on days 1-5) with or without bevacizumab (10 mg/kg IV on days 1 and 15). RESULTS: One hundred five patients were eligible and treated on study. Median OS was 13 months in the standard arm and 19 months with the addition of bevacizumab; median event-free survival (EFS) was 6 months in the standard arm and 9 months with the addition of bevacizumab. The hazard ratio for death from the stratified relative-risk regression model is 0.63. Overall, 23 patients completed 12 courses of planned protocol therapy, 23% (12/52) in the experimental arm with bevacizumab versus 21% (11/53) in the standard arm. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is three of 52 (5.8%) (95% CI 1.2-16%). Events included myelosuppression, electrolyte abnormalities, diarrhea, and elevated transaminases. One intracranial hemorrhage event was observed in each arm. CONCLUSION: The addition of bevacizumab to TMZ/irinotecan significantly reduced the risk of death in children with recurrent MB. The combination was relatively well tolerated in this heavily pretreated cohort. The three-drug regimen demonstrated a sufficient risk reduction to warrant further investigation.

Chlorhexidine gluconate bathing in children with cancer or those undergoing hematopoietic stem cell transplantation: A double-blinded randomized controlled trial from the Children's Oncology Group.

BACKGROUND: To the authors' knowledge, information regarding whether daily bathing with chlorhexidine gluconate (CHG) reduces central line-associated bloodstream infection (CLABSI) in pediatric oncology patients and those undergoing hematopoietic stem cell transplantation (HCT) is limited. METHODS: In the current multicenter, randomized, double-blind, placebo-controlled trial, patients aged ≥2 months and <22 years with cancer or those undergoing allogeneic HCT were randomized 1:1 to once-daily bathing with 2% CHG-impregnated cloths or control cloths for 90 days. The primary outcome was CLABSI. Secondary endpoints included total positive blood cultures, acquisition of resistant organisms, and acquisition of cutaneous staphylococcal isolates with an elevated CHG mean inhibitory concentration. RESULTS: The study was stopped early because of poor accrual. Among the 177 enrolled patients, 174 were considered as evaluable (88 were randomized to the CHG group and 86 were randomized to the control group). The rate of CLABSI per 1000 central line days in the CHG group was 5.44 versus 3.10 in the control group (risk difference, 2.37; 95% confidence interval, 0.05-4.69 [P = .049]). Post hoc conditional power analysis demonstrated a 0.2% chance that the results would have favored CHG had the study fully enrolled. The rate of total positive blood cultures did not differ between groups (risk difference, 2.37; 95% confidence interval, -0.41 to 5.14 [P = .078]). The number of patients demonstrating the new acquisition of resistant organisms did not differ between groups (P = .54). Patients in the CHG group were found to be more likely to acquire cutaneous staphylococcal isolates with an elevated CHG mean inhibitory concentration (P = .032). CONCLUSIONS: The data from the current study do not support the use of routine CHG bathing in children with cancer or those undergoing allogeneic HCT.

A Randomized Trial of Caspofungin vs Triazoles Prophylaxis for Invasive Fungal Disease in Pediatric Allogeneic Hematopoietic Cell Transplant.

BACKGROUND: Children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) are at high risk for invasive fungal disease (IFD). METHODS: This multicenter, randomized, open-label trial planned to enroll 560 children and adolescents (3 months to <21 years) undergoing allogeneic HCT between April 2013 and September 2016. Eligible patients were randomly assigned to antifungal prophylaxis with caspofungin or a center-specific comparator triazole (fluconazole or voriconazole). Prophylaxis was administered from day 0 of HCT to day 42 or discharge. The primary outcome was proven or probable IFD at day 42 as adjudicated by blinded central review. Exploratory analysis stratified this evaluation by comparator triazole. RESULTS: A planned futility analysis demonstrated a low rate of IFD in the comparator triazole arm, so the trial was closed early. A total of 290 eligible patients, with a median age of 9.5 years (range 0.3-20.7), were randomized to caspofungin (n = 144) or a triazole (n = 146; fluconazole, n = 100; voriconazole, n = 46). The day 42 cumulative incidence of proven or probable IFD was 1.4% (95% confidence interval [CI], 0.3%-5.4%) in the caspofungin group vs 1.4% (95% CI, 0.4%-5.5%) in the triazole group (P = .99, log-rank test). When stratified by specific triazole, there was no significant difference in proven or probable IFD at day 42 between caspofungin vs fluconazole (1.0%, 95% CI, 0.1%-6.9%, P = .78) or caspofungin vs voriconazole (2.3%, 95% CI, 0.3%-15.1%, P = .69). CONCLUSIONS: In pediatric HCT patients, prophylaxis with caspofungin did not significantly reduce the cumulative incidence of early proven or probable IFD compared with triazoles. Future efforts to decrease IFD-related morbidity and mortality should focus on later periods of risk. TRIAL REGISTRATION: NCT01503515.

Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial.

Importance: Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. Objective: To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. Design, Setting, and Participants: This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Interventions: Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. Main Outcomes and Measures: The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. Results: The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Conclusions and Relevance: Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. Trial Registration: ClinicalTrials.gov Identifier: NCT01307579.

α-Fetoprotein as a predictor of outcome for children with germ cell tumors: A report from the Malignant Germ Cell International Consortium.

BACKGROUND: There are several studies describing the correlation between unsatisfactory tumor marker decline and a poor prognosis for adult patients treated for germ cell tumors. In pediatric patients, the data are limited. Therefore, this study retrospectively analyzed data from Children's Oncology Group (COG) protocol AGCT0132 to determine whether a relationship exists between α-fetoprotein (AFP) decline and outcome. METHODS: One hundred thirty-one patients with germ cell tumors who were enrolled in COG protocol AGCT0132 were eligible for this analysis of AFP decline. The serum AFP half-life was calculated from levels collected postoperatively as a baseline and after the start of chemotherapy. AFP decline was defined as automatically satisfactory (AFP normalized within the first 2 AFP measures after the start of chemotherapy), calculated satisfactory (AFP half-life ≤7 days after the start of chemotherapy), and unsatisfactory. RESULTS: The 3-year cumulative incidence of relapse was 11% (95% confidence interval [CI], 6.0%-18%) for patients with a satisfactory decline and 38% (95% CI, 13%-64%) for patients with an unsatisfactory decline (P = .006). In stratified analyses, this effect was limited to patients who were 11 years of age or older and had standard risk 2 (SR2) disease (P = .004 and P = .007, respectively). Three-year overall survival (OS) for patients with a satisfactory decline versus an unsatisfactory decline was not statistically significant. CONCLUSIONS: This study is the first to show an association between AFP decline and the cumulative incidence of relapse in pediatric patients treated for germ cell tumors. Recognition of patients at high risk for relapse may allow for early intensification of therapy, which could affect future clinical trial design.

A phase II study of eribulin in recurrent or refractory osteosarcoma: A report from the Children's Oncology Group.

BACKGROUND: Patients with recurrent or refractory osteosarcoma have a poor prognosis with less than 30% surviving two years. Eribulin is a synthetic analog of halichondrin B, has a novel mechanism of action when compared with other microtubule inhibitors, and may have antitumor activity in osteosarcoma. METHODS: A prospective study was designed to assess the disease control success at four months and objective response rates in patients with recurrent or refractory osteosarcoma treated with eribulin. Eligible patients were between 12 and 50 years of age, had measurable tumor, and met standard organ function requirements. Patients were given eribulin 1.4 mg/m2 /dose on days 1 and 8 of each 3-week cycle for up to 24 months if there was no progressive disease. Response to therapy was assessed using RECIST 1.1 criteria after cycles 2 and 5 and every fourth cycle thereafter. RESULTS: Nineteen patients enrolled on the AOST1322 study. The median age of enrollment was 16 years (range, 12-25 years). Twelve patients were male and seven female. Eribulin was well tolerated, with neutropenia identified as the most common toxicity. The median progression-free survival was 38 days and no patients reached the four-month time point without progression. No objective responses were seen in any patient. CONCLUSION: This study rapidly assessed the clinical activity of a novel agent in this patient population. Eribulin was well tolerated, but there were no patients who demonstrated objective response, and all patients had progression prior to four months.

Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study.

Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.

Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children's Oncology Group.

Purpose To investigate whether event-free survival (EFS) can be maintained among children and adolescents with intermediate-risk (IR) malignant germ cell tumors (MGCT) if the administration of cisplatin, etoposide, and bleomycin (PEb) is reduced from four to three cycles and compressed from 5 to 3 days per cycle. Patients and Methods In a phase 3, single-arm trial, patients with IR MGCT (stage II-IV testicular, II-III ovarian, I-II extragonadal, or stage I gonadal tumors with subsequent recurrence) received three cycles of PEb. A parametric comparator model specified that the observed EFS rate should not be significantly < 92%. As recommended for trials that test a reduction of therapy, a one-sided P value ≤ .10 was used to indicate statistical significance. In a post hoc analysis, we also compared results to the EFS rate of comparable patients treated with four cycles of PEb in two prior studies. Results Among 210 eligible patients enrolled from 2003 to 2011, 4-year EFS (EFS4) rate was 89% (95% confidence interval, 83% to 92%), which was significantly lower than the 92% threshold of the comparison model ( P = .08). Among 181 newly diagnosed patients, the EFS4 rate was 87%, compared with 92% for 92 comparable children in the historical cohort ( P = .15). The EFS4 rate was significantly associated with stage (stage I, 100%; stage II, 92%; stage III, 85%; and stage IV, 54%; P < .001). Conclusion The EFS rate for children with IR MGCT observed after three cycles of PEb was less than that of a prespecified parametric model, particularly for patients with higher-stage tumors. These data do not support a reduction in the number of cycles of PEb from four to three. However, further investigation of a reduction in the number of cycles for patients with lower-stage tumors is warranted.

Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents. METHODS: ACCL0431 was a multicentre, randomised, open-label, phase 3 trial that enrolled participants at 38 participating Children's Oncology Group hospitals in the USA and Canada. Eligible participants aged 1-18 years with newly diagnosed cancer and normal audiometry were randomly assigned (1:1) to receive sodium thiosulfate or observation (control group) in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of four. Randomisation was initially stratified by age and duration of cisplatin infusion. Stratification by previous cranial irradiation was added later as a protocol amendment. The allocation sequence was computer-generated centrally and concealed to all personnel. Participants received sodium thiosulfate 16 g/m2 intravenously 6 h after each cisplatin dose or observation. The primary endpoint was incidence of hearing loss 4 weeks after final cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria but treatment was not masked for participants or clinicians. Analysis of the primary endpoint was by modified intention to treat, which included all randomly assigned patients irrespective of treatment received but restricted to those assessable for hearing loss. Enrolment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976. FINDINGS: Between June 23, 2008, and Sept 28, 2012, 125 eligible participants were randomly assigned to either sodium thiosulfate (n=61) or observation (n=64). Of these, 104 participants were assessable for the primary endpoint (sodium thiosulfate, n=49; control, n=55). Hearing loss was identified in 14 (28·6%; 95% CI 16·6-43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3-69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13-0·73; p=0·0036). The most common grade 3-4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 177 participant cycles in the sodium thiosulfate group vs 145 [65%] of 223 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 147 vs 22 [12%] of 187). Of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were deemed probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count: 26 episodes in 14 participants. INTERPRETATION: Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies. FUNDING: US National Cancer Institute.

Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): A report from the Children's Oncology Group.

PURPOSE: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. PATIENTS AND METHODS: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. RESULTS: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. CONCLUSIONS: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.

Assessment of extent of surgical resection of primary high-grade osteosarcoma by treating institutions: A report from the Children's Oncology Group.

BACKGROUND: Complete surgical resection of primary tumors is critical for long-term control of high-grade osteosarcoma. Uniform assessment of the extent of surgical resection is important in clinical trials, though the accuracy of this reporting has been poorly studied. METHODS: We conducted a retrospective cohort study of patients 5-40 years of age with newly diagnosed high-grade resectable osteosarcoma treated as part of the AOST0331 clinical trial at Children's Oncology Group institutions. The extent of surgical resection of the primary tumor was graded as wide or radical by the treating institution. Central assessment of the extent of resection by two orthopedic oncologists was compared with institutional assessment by reviewing pathology and operative reports. RESULTS: We included 956 patients who had data available for central review. The extent of resection reported by treating institutions was 536/956 (56%) radical and 420/956 (44%) wide. The extent of resection assessed by central review was 162/956 (17%) radical and 794/956 (83%) wide. The overall discordance rate for the cohort was 43%. CONCLUSIONS: Institutional reports of radical resection in high-grade osteosarcoma significantly over-estimate the proportion of patients undergoing radical resection. This highlights the need for centralized review and improved accuracy of reporting of the extent of resection. J. Surg. Oncol. 2016;113:351-354. © 2016 Wiley Periodicals, Inc.

Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.

BACKGROUND: The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. PROCEDURE: Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). RESULTS: Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). CONCLUSIONS: The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Feasibility Study of a Novel Experimental Induction Protocol Combining B43-PAP (Anti-CD19) Immunotoxin With Standard Induction Chemotherapy in Children and Adolescents With Relapsed B-Lineage ALL: A Report From the Children's Oncology Group.

BACKGROUND: B43-pokeweed antiviral protein (B43-PAP) is a high-affinity anti-CD19 immunotoxin that is capable of causing apoptotic death in B-lineage leukemic cells with a drug-resistant phenotype. B43-PAP exhibited in vivo antileukemic activity in preclinical studies as well as on a single-agent phase I clinical trial. This pediatric phase I/II study evaluated the toxicity profile and efficacy of B43-PAP immunotoxin in combination with standard induction chemotherapy in children and adolescents with relapsed CD19-positive B-lineage acute lymphoblastic leukemia (B-ALL). Pharmacokinetic profile and immunogenicity of B43-PAP were assessed. EXPERIMENTAL DESIGN: B43-PAP in combination with standard 3 and 4-drug induction chemotherapy was administered on days 9-13 and 21-25 of a 28-day treatment course with vincristine, prednisone, L-asparaginase, daunomycin, and intrathecal methotrexate. Thirty patients with relapsed B-ALL were enrolled on study CCG-0957. RESULTS: Grade III/IV nonhematologic dose-limiting toxicities were encountered in 4 patients evaluable for toxicity and included myalgias, motor dysfunction, pulmonary toxicity, and elevated liver transaminase. Dose-limiting toxicities occurred only with the 4-drug regimen. Fourteen patients achieved a complete remission at the end of induction among the 20 patients evaluable for response. CONCLUSIONS: B43-PAP in combination with standard induction chemotherapy can be safely administered and exhibits clinical antileukemic activity against relapsed B-ALL.

Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: Report from the Children's Oncology Group.

PURPOSE: The purpose of this study was to determine prognostic factors correlating with outcome in boys with Stage I malignant testicular germ cell tumors (MTGCT) initially managed with surveillance after surgical resection. METHODS: Between November 2003 and July 2011, 80 boys 0-15 years with Stage I MTGCT were enrolled in Children's Oncology Group Study AGCT0132. Those with residual or recurrent disease were treated with chemotherapy. RESULTS: Characteristics include: age (65, 0-5 years and 15, 11+years), pure YST (93.9%, 0-5 years and 0%, 11+years); and lymphovascular invasion (LVI) (50.6% present vs. 49.4% absent). At median follow-up of 4.94 years, 19 had persistent or recurrent disease, all detected by elevated AFP at a median of 87 days after study enrollment. The outcome from enrollment was 4-year EFS 74% (95% CI: 63%-83%) and 4-year OS 100%. 4-year EFS was improved with younger age (<11 years, 80% vs. 11+years, 48%, p<0.01); pure YST vs. mixed histology (81% vs. 45%, p<0.01), and lack of LVI (84% vs. 62%, p=0.03). CONCLUSIONS: Boys with Stage I MTGCT have excellent overall survival when treated with surgery alone. Age greater than 10 years, mixed histology and presence of LVI are each associated with relapse and may allow identification of high risk boys at time of enrollment.

Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children's Oncology Group.

PURPOSE: To determine whether overall survival (OS) can be preserved for patients with stage I pediatric malignant ovarian germ cell tumor (MOGCT) with an initial strategy of surveillance after surgical resection. PATIENTS AND METHODS: Between November 2003 and July 2011, girls age 0 to 16 years with stage I MOGCT were enrolled onto Children's Oncology Group study AGCT0132. Required histology included yolk sac, embryonal carcinoma, or choriocarcinoma. Surveillance included measurement of serum tumor markers and radiologic imaging at defined intervals. In those with residual or recurrent disease, chemotherapy with compressed PEB (cisplatin, etoposide, and bleomycin) was initiated every 3 weeks for three cycles (cisplatin 33 mg/m(2) on days 1 to 3, etoposide 167 mg/m(2) on days 1 to 3, bleomycin 15 U/m(2) on day 1). Survivor functions for event-free survival (EFS) and OS were estimated using the Kaplan-Meier method. RESULTS: Twenty-five girls (median age, 12 years) with stage I MOGCT were enrolled onto AGCT0132. Twenty-three patients had elevated alpha-fetoprotein (AFP) at diagnosis. Predominant histology was yolk sac. After a median follow-up of 42 months, 12 patients had evidence of persistent or recurrent disease (4-year EFS, 52%; 95% CI, 31% to 69%). Median time to recurrence was 2 months. All patients had elevated AFP at recurrence; six had localized disease, two had metastatic disease, and four had tumor marker elevation only. Eleven of 12 patients experiencing relapse received successful salvage chemotherapy (4-year OS, 96%; 95% CI, 74% to 99%). CONCLUSION: Fifty percent of patients with stage I pediatric MOGCT can be spared chemotherapy; treatment for those who experience recurrence preserves OS. Further study is needed to identify the factors that predict recurrence and whether this strategy can be extended successfully to older adolescents and young adults.