Children's Cancer Group Research Articles

Poorer Relapse-Free Survival in Hispanic Children Diagnosed with Acute Myeloid Leukemia Compared with Non-Hispanics: A Texas Single Institution Experience

Introduction: Acute myeloid leukemia (AML) comprises about 18% of childhood leukemias, with an incidence of 7.7 cases per million in the United States. The evidence for variation in disease distribution by race and ethnicity is limited, although there is a slight increased risk for the promyelocytic subtype in Hispanics (Puumala et al, Pediatr Blood Cancer, 2014). In earlier treatment eras (pre-2002), the Children's Cancer Group reported Hispanics with AML to have inferior overall survival (OS) when compared with non-Hispanics (Lange et al, Blood, 2008; Aplenc et al, Blood, 2006), but their event-free survival did not differ significantly. According to recent SEER data, both Hispanic children and adults with AML demonstrated similar OS disparities (Hossain et al, Cancer Epidemiol, 2015; Patel et al, Am J of Clin Oncol, 2015), despite the fact that age at presentation and cytogenetic features were more favorable in Hispanics compared with non-Hispanics. In order to better understand the impact of Hispanic ethnicity upon AML outcomes, we examined relapse-free survival (RFS) and OS in children diagnosed with AML at Texas Children's Hospital (TCH), which has a large Hispanic population, and compared host, disease, and treatment factors that may have affected outcomes.Methods: We retrospectively reviewed medical records from children (age 0-21 years) with newly diagnosed AML treated at TCH between 1998 and 2015. Subjects with acute promyelocytic leukemia or therapy-related AML were excluded. Self-reported race and ethnicity were used to categorize the study population into Hispanics (of any race) and non-Hispanics. Differences in proportions of host, disease, and treatment characteristics between the two groups were compared using Pearson's X2 test. The Kaplan-Meier method was applied to estimate RFS and OS. We then used the Wilcoxon-Breslow-Gehan test to determine if survival functions (RFS and OS) were statistically different by ethnicity, adjusting for treatment era (pre-vs, post 2002). RFS was defined as time from the date of diagnosis until date of relapse. Patients without an event were censored at the date of last known contact. Research was performed under a local Institutional Review Board-approved protocol and in accord with the Declaration of Helsinki.Results: Of the 99 AML cases with available clinical information, 37 (37%) self-identified as Hispanic. Host, disease, and treatment factors in Hispanic and non-Hispanic subjects with AML did not differ according to prognostic factors such as age at diagnosis or favorable cytogenetic features (Table 1). Additionally, Hispanics and non-Hispanics did not differ significantly in cause of death (disease-related or other). The groups did not differ significantly in OS, but Hispanics had significantly poorer RFS (p=0.03) (Figure 1).Conclusions: Despite no significant differences in frequency of known AML risk factors, the TCH Hispanic population was both significantly more likely to relapse and had an earlier time to relapse than did non-Hispanics. This effect was even more surprising given that this population was twice as likely to have AML characterized by favorable cytogenetic features, although this enrichment did not reach significance. Of note, the RFS difference we observed is unlikely to be related to treatment compliance or socioeconomic factors, as all AML patients were hospitalized throughout treatment. Further study is needed to confirm this finding in a larger pediatric AML cohort, and to identify host factors related to Hispanic ancestry that may be responsible for the differences observed in RFS. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Does the early intensification of intrathecal therapy improve outcomes in pediatric acute lymphoblastic leukemia patients with CNS2/TLP+ status at diagnosis?

ObjectivesWe aimed to determine whether the addition of two extra intrathecal methotrexate (ITM) doses during induction in acute lymphoblastic leukemia (ALL) patients eliminate the prognostic significance of CNS2/TLP+ status.MethodsWe retrospectively analyzed 224 patients according to the central nervous system (CNS) involvement at diagnosis: CNS1, CNS2, or CNS3. Patients with CNS2/TLP+ received two additional ITM doses during induction. Patients were treated according to the Children's Cancer Group (CCG)-1991/1961 protocols between January 2001 and December 2007.ResultsThe 5-year relapse-free survival (RFS) rates for the ALL patients in the CNS1, CNS2, and CNS3 groups were 80.4 ± 3.0, 100, and 73.5 ± 11.3%, respectively; a non-significant difference was observed between the groups (P = 0.063). However, the patients with CNS2 had significantly better survival compared with the CNS3 patients (P = 0.03). The 5-year cumulative incidence of relapse (CIR) rates for the three groups were 17 (95% confidence interval (CI): 11.9–22.9), 0, and 18.8% (95% CI: 4.3–41.1), respectively; (P = 0.214) and those of isolated or combined CNS relapse were 9.6 (95% CI: 5.8–14.5), 0 and 6.3% (95% CI: 0.3–25.8), respectively (P = 0.424).ConclusionsThis study shows that the intensification of ITM therapy during induction improves outcomes in patients with CNS2/TLP+ status and eliminates its prognostic significance. This suggests that early intensification using CNS-directed therapy is beneficial in controlling minimal CNS disease.

Dosimetric Comparison and Potential for Improved Clinical Outcomes of Paediatric CNS Patients Treated with Protons or IMRT.

Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. Methods: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. Results: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. Conclusions: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects.

Pilot Study of Intensive Chemotherapy With Peripheral Hematopoietic Cell Support for Children Less Than 3 Years of Age With Malignant Brain Tumors, the CCG-99703 Phase I/II Study. A Report From the Children's Oncology Group

BackgroundThe primary goals of the Children's Cancer Group 99703 study were to assess the feasibility and tolerability of—as well as the response rate to—a novel dose-intensive chemotherapy regimen. MethodsBetween March 1998 and October 2004, 92 eligible patients were enrolled. Following biopsy/resection, patients received three identical cycles of Induction chemotherapy (vincristine, cyclophosphamide, etoposide, and cisplatin) administered every 21-28 days. Patients without tumor progression then received three consolidation cycles of marrow-ablative chemotherapy (thiotepa and carboplatin) followed by autologous hematopoietic cell rescue. ResultsThe maximum tolerated dose of thiotepa was 10 mg/kg/day × 2 days per cycle. The toxic mortality rate was zero during induction and 2.6% during consolidation. Centrally evaluated response rates to induction and consolidation in evaluable patients with residual tumor were 73.3% and 66.7%, respectively. Disease progression rates on induction and consolidation were 4%. Five-year event-free survival and overall survival were 43.9 ± 5.2% and 63.6 ± 5% respectively. Gross total resection versus less than gross total resection were the only significant outcome comparisons: 5-year maximum tolerated dose and overall survival of 54.4 ± 7% versus 28.9 ± 7% (P = 0.0065) and 75.9 ± 8% versus 48.7 ± 8% (P = 0.0034), respectively. The 5-year maximum tolerated dose for localized (M0) versus metastatic (M1+) medulloblastoma was 67.5 ± 9.5% versus 30 ± 14.5% (P = 0.007). The 5-year maximum tolerated dose and overall survival for desmoplastic medulloblastoma patients versus other medulloblastoma were 78.6 ± 11% versus 50.5 ± 12% (P = 0.038) and 85.7 ± 9.4% versus 60.6 ± 11.6% (P = 0.046), respectively. ConclusionsThis phase I dose-escalation study of marrow-ablative thiotepa regimen determined a maximum tolerated dose that had acceptable toxicity. Overall survival data justify this strategy for current Children's Oncology Group studies.

Commentary on: "A Multi-Institutional Experience in Pediatric High Grade Glioma".

Commentary on: "A Multi-Institutional Experience in Pediatric High Grade Glioma".

Identifying causes of variability in outcomes in children with acute lymphoblastic leukemia treated in a resource-rich developing country.

The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource-rich developing countries would be similar to those in industrialized regions. We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children's Cancer Group (CCG) protocols between January 2001 and December 2007. High-risk (HR) and standard-risk (SR) patients were treated with modified CCG-1961 and CCG-1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases. Five-year overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 84.7 ± 2.4%, 77.0 ± 2.9%, and 81.4 ± 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time. Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions.

Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945.

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.

MicroRNA signatures as biomarkers and therapeutic target for CNS embryonal tumors: the pros and the cons.

Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5–10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets.

Analysis of childhood leukemia mortality trends in Brazil, from 1980 to 2010

ObjectiveLeukemias comprise the most common group of cancers in children and adolescents. Studies conducted in other countries and Brazil have observed a decrease in their mortality. This study aimed to evaluate the trend of mortality from leukemia in children under 19 years of age in Brazil, from 1980 to 2010. MethodsThis was an ecological study, using retrospective time series data from the Mortality Information System, from 1980 to 2010. Calculations of mortality rates were performed, including gross, gender‐specific, and age‐based. For trend analysis, linear and semi‐log regression models were used. The significance level was 5%. ResultsMortality rates for lymphoid and myeloid leukemias presented a growth trend, with the exception of lymphoid leukemia among children under 4 years of age (percentage decrease: 1.21% annually), while in the sub‐group “Other types of leukemia”, a downward trend was observed. Overall, mortality from leukemia tended to increase for boys and girls, especially in the age groups 10‐14 years (annual percentage increase of 1.23% for males and 1.28% for females) and 15‐19 years (annual percentage increase of 1.40% for males and 1.62% for females). ConclusionsThe results for leukemia generally corroborate the results of other similar studies. A detailed analysis by subgroup of leukemia, age, and gender revealed no trends shown in other studies, thus indicating special requirements for each variable in the analysis.

A prospective study of the hypothalamic-pituitary-adrenal axis in children with acute lymphoblastic leukemia receiving chemotherapy

BackgroundGlucocorticoids are essential in protocols of therapy of acute lymphoblastic leukemia (ALL).ObjectivesTo assess the incidence, severity, morbidity, and risk factors of hypothalamic-pituitary-adrenal axis (HPA) suppression in children with ALL, and the time course of recovery.DesignForty standard risk ALL children treated in the Pediatric Hematology/Oncology Unit, Ain-Shams University, Egypt, were classified into dexamethasone (DXM) group: 20 patients on children cancer group protocol and prednisone (PDN) group: 20 patients on modified Berlin-Frankfurt-Muenster (BFM) study group 90 protocol. Patients were followed clinically and by laboratory assessment of morning s.ACTH, basal and after low-dose adrenocorticotrophic hormone stimulation test of cortisol and DHEAS, at diagnosis and every 2 weeks till adrenal recovery.ResultsHPA recovery was earlier in PDN than DXM group (P < 0.05). In induction phases 1 and 2: 65 and 75% of PDN group recovered on week 2, while 45 and 50% of DXM group recovered in week 4. Adrenal recovery was predicted 2 weeks earlier by normalized s.DHEAS. Children below 5 years of age had earlier recovery in PDN group (P = 0.04), no age effect in DXM group.ConclusionAdrenal suppression is an inevitable consequence of ALL therapy. Monitoring of cortisol levels and steroid coverage during stress is recommended, and gradual steroid tapering is suggested.

THOR METHYLATION PROVIDES INSIGHT INTO THE TELOMERE MAINTENANCE LANDSCAPE OF MALIGNANT GLIOMAS

BACKGROUND: Gliomas are a deadly group of childhood and adult cancers associated with high relapse rate following current therapies. Limitless self-renewal is a hallmark of cancer recurrence and is controlled by telomerase activation and telomere maintenance. We have recently uncovered THOR (TERT Hypermethylated Oncological Region) which is paradoxically hypermethylated in gliomas with telomerase activation. In order to further explore the biological impact of THOR hypermethylation on self renewal and telomere maintenance of gliomas we undertook a stepwise approach. METHODS: RESULTS: Mapping of the human TERT promoter reveals that THOR spans 432 BP and comprises 52 CG sites. In contrast, the area where mutations in TERT promoter were uncovered is permanently hypomethylated. Promoter driven expression was analysed through luciferase assays and unveiled a repressive effect of THOR on the TERT promoter. Moreover, TERT mutations promoted hyperactivation of the reporter gene providing explanations for the methylation pattern observed in malignant gliomas. THOR methylation increases in gliomas as they transform from low to high grade and from primary tumor to established cell lines (p < 0.001). Analysis of allelic Tert expression reveals that THOR is initally methylated in the mutant allele and throughout tumor progression, the other allele eventually becomes methylated. This correlates with higher TERT expression. In contrast, tumors utilizing alternative lengthening of telomeres (ALT) lack THOR methylation and TERT mutations. Glioma stem cells (n = 32) are addicted to telomerase and have higher THOR methylation than the bulk tumor. Strikingly, glioblastomas which activate ALT lack this phenotype in their stem cells compartment. Whole exome sequencing reveals multiple ALT related mutations (TP53 and ATRX) which are present in the mature tumor cells subpopulation and absent in the TERT expressing stem cell subpopulation. THOR demethylation with Decitabine results in loss of telomerase activation only in tumor cells and not in normal and embryonic stem cells which lack THOR methylation. Combining telomerase inhibition with decitabine result in permanent loss of self renewal capacity of patient derived cell lines in vitro and lack of tumor formation in vivo. CONCLUSIONS: We offer a model and a novel classification of gliomas based on THOR hypermethylation and alterations in the telomere maintenance pathway. We also suggest that intratumoral heterogeneity in telomere maintenance might be the result of secondary hits in the non-stem cell compartment Finally, we propose that THOR demethylation can be a safe and viable option for exhausting the self renewal capacity of gliomas. SECONDARY CATEGORY: Pediatrics.

Analysis of childhood leukemia mortality trends in Brazil, from 1980 to 2010

ObjectiveLeukemias comprise the most common group of cancers in children and adolescents. Studies conducted in other countries and Brazil have observed a decrease in their mortality.This study aimed to evaluate the trend of mortality from leukemia in children under 19 years of age in Brazil, from 1980 to 2010. MethodsThis was an ecological study, using retrospective time series data from the Mortality Information System, from 1980 to 2010. Calculations of mortality rates were performed, including gross, gender-specific, and age-based. For trend analysis, linear and semi-log regression models were used. The significance level was 5%. ResultsMortality rates for lymphoid and myeloid leukemias presented a growth trend, with the exception of lymphoid leukemia among children under 4 years of age (percentage decrease: 1.21% annually), while in the sub-group “Other types of leukemia”, a downward trend was observed. Overall, mortality from leukemia tended to increase for boys and girls, especially in the age groups 10-14 years (annual percentage increase of 1.23% for males and 1.28% for females) and 15-19 years (annual percentage increase of 1.40% for males and 1.62% for females). ConclusionsThe results for leukemia generally corroborate the results of other similar studies. A detailed analysis by subgroup of leukemia, age, and gender revealed no trends shown in other studies, thus indicating special requirements for each variable in the analysis.

The contribution of neurocognitive functioning to quality of life after childhood acute lymphoblastic leukemia

Neurocognitive late effects after childhood acute lymphoblastic leukemia (ALL) are well-documented, but their impact on quality of life (QOL) is not well understood. In this multi-site study, we examined the relative influence of neurocognitive functioning, steroid randomization (prednisone vs. dexamethasone), and demographic characteristics on QOL in first-remission survivors of childhood ALL. Participants included 263 ALL survivors (ages 7-17 years at the time of evaluation; mean age at diagnosis 3.9 years) who were treated on similar legacy Children's Cancer Group chemotherapy protocols and did not receive cranial radiation. Children completed detailed neuropsychological performance tests. The Pediatric QOL Inventory was completed by children and their parents. Participants were a mean of 9 years from diagnosis at the time of assessment (with a range of 4 to 13 years). Children and their parents reported lower mean child psychosocial QOL than healthy population norms (p < 0.05), but were not in the impaired range. Physical QOL was similar to population norms. Though neurocognitive difficulties were predominantly mild for the sample as a whole, neurocognitive deficits, specifically problems in verbal cognitive abilities and visual-motor integration skills, were significantly associated with poor physical (p < 0.01) and Psychosocial QOL (p < 0.01). QOL was not associated with previous steroid randomization. ALL survivors with neurocognitive deficits are at risk for poor QOL, with broad implications for their physical, social, and school functioning.

UK case control study of brain tumours in children, teenagers and young adults: a pilot study.

BackgroundTumours of the central nervous system are the second most common group of childhood cancers in 0–14 year olds (24% of total cancers) and represent a major diagnostic group in 15–24 year olds. The pilot case–control study aimed to establish methodologies for a future comprehensive aetiological investigation among children and young adults.MethodsEligible cases were newly diagnosed with an intracranial tumour of neuroepithelial tissue aged 0–24 years. The pilot recruited patients through Leeds and Manchester Principal Treatment Centres. Controls were drawn from general practice lists. Controls were frequency matched by age and gender.ResultsWe interviewed 49 cases and 78 controls comprising 85% of the target sample size. Response rates were 52% for cases and 32% for controls. Completion of the questionnaire was successful, with a very small proportion of missing data being reported (5-10%). The age distribution of cases and controls was similar with around three-quarters of interviewed subjects aged 0–14. Half of cases and almost two-thirds of controls reported using a mobile phone with the majority starting between 10–14 years of age. Prevalence of breastfeeding was lower in cases than controls (Odds Ratio 0.4; 95% CI 0.2-1.2), whilst cases were more likely to be delivered by caesarean section (OR 1.6; 95% CI 0.6-4.4). Cases were significantly more likely to have a birthweight > 3.5 kg compared to controls. Cases were also more likely to come from a family with 3 or more siblings than controls (OR 3.0; 95% CI 0.7-13.6). The majority of participants (>80%) were in favour of taking either blood or saliva to aid molecular epidemiological research.ConclusionsSuccessful methods were established for identifying and recruiting a high proportion of case subjects, exploiting strong links with the clinical teams at the treatment centres. Control procedures proved more difficult to implement. However, working closely with national clinical and professional research networks will enable improved control identification and recruitment, with good prospects for collecting biological samples in the future.

Childhood cancer in Africa

The majority of children with cancer live in low- and middle-income countries (LMICs) with little or no access to cancer treatment. The purpose of the paper is to describe the current status of childhood cancer treatment in Africa, as documented in publications, dedicated websites and information collected through surveys. Successful twinning programmes, like those in Malawi and Cameroon, as well as the collaborative clinical trial approach of the Franco-African Childhood Cancer Group (GFAOP), provide good models for childhood cancer treatment. The overview will hopefully influence health-care policies to facilitate access to cancer care for all children in Africa.

Differences in outcomes of newly diagnosed acute myeloid leukemia for adolescent/young adult and younger patients

Studies comparing survival of adolescent and young adult (AYA) patients to that of younger patients with newly diagnosed acute myeloid leukemia (AML) have yielded conflicting results. In order to more accurately characterize relative survival and other outcomes of AYA patients, a cross-study analysis was conducted using data from recent trials conducted by the Children's Cancer Group (CCG) and Children's Oncology Group (COG). Data were combined from the CCG-2891, CCG-2941, CCG-2961, and AAML03P1 trials. The data set included 1840 patients, comprising 238 AYA and 1602 younger patients. Overall survival was not significantly different in the 2 groups (AYA, 49% ± 7% versus younger, 54% ± 3% (± 2 standard errors), P = .058). Relapse was lower in AYA patients (30% ± 7% versus 41% ± 3%, P = .002), but treatment-related mortality (TRM) was higher (25% ± 6% versus 12% ± 2%, P < .001). After adjustment for other factors, older age remained strongly associated with TRM (hazard ratio = 2.30, 95% CI = 1.59-3.33, P < .001). Infection accounted for the excess TRM in AYA patients. Survival in AYA and younger patients with newly diagnosed AML is similar; however, older patients are at higher risk for TRM. More effective strategies for preventing mortality from infection in AYA patients are needed.

Is Radiotherapy Needed for Pediatric Hodgkin Lymphoma?

TO THE EDITOR: Dorffel et al recently reported results from the nonrandomized phase II German Society of Pediatric Oncology and Hematology–Hodgkin’s Disease 95 (GPOH-HD95) trial involving the omission of radiotherapy for children and adolescents with Hodgkin lymphoma. They conclude that radiotherapy can be safely omitted in early-stage Hodgkin lymphoma in patients with a complete response. This statement does not seem justified. Compared with their historical standard, Deutschen Arbeitsgemeinschaft fur Leukamieforschung–Hodgkin’s Disease 90 (DALHD90), radiotherapy significantly improved 10-year progression-free survival (PFS; 92% v 84%; P .004) for all 165 patients. In the patient subset with early-stage disease (n 66), radiotherapy did not improve PFS. Can the omission of radiotherapy be based on 66 patients compared with a historical control? More than 10 times as many patients are needed to show noninferiority. For example, Hodgkin’s Disease 11 (HD11) was a noninferiority trial that involved 1,395 adult patients, and found that 20 Gy of radiotherapy was inferior to 30 Gy. Dorffel et al claim that their results are consistent with those of previous randomized trials. The Children’s Cancer Group (CCG) conducted a phase III trial evaluating whether radiotherapy could be omitted with a complete response after chemotherapy. The trial met early stopping rules because the event-free survival (EFS) was inferior in children who did not receive radiotherapy. The EFS difference of 91.2% versus 82.9% (P .004) in favor of radiotherapy persisted at 10 years, although the 10-year overall survival difference did not reach statistical significance. Overall survival requires more power than EFS because the event rate is lower. Thus, because the CCG trial closed early as a result of inferior results without radiotherapy, it lacked power to show an overall survival benefit. In my opinion, both trials indicate that radiotherapy is required in Hodgkin lymphoma, whereas the authors conclude the opposite. The combination of chemotherapy and radiotherapy should continue to be the standard of care for patients with pediatric Hodgkin lymphoma.

Long‐term survival of children less than six years of age enrolled on the CCG‐945 phase III trial for newly‐diagnosed high‐grade glioma: A report from the Children's Oncology Group

We analyzed the long-term survival of children under 6 years of age (<6 years) enrolled upon the Children's Cancer Group (CCG)-945 high-grade glioma (HGG) study to determine the impact of intrinsic biological characteristics as well as treatment upon both survival and quality of life (QOL) in this younger age population. Analyses were undertaken on patients <6 years with institutionally diagnosed HGG enrolled on the CCG-945 trial. Comparisons of survival were performed for patients <3 years of age (<3 years) (treated with intent to avoid irradiation) versus those between 3 and 6 years of age (3-6 years) (treated with irradiation and chemotherapy) at diagnosis. Discordance between the institutional diagnoses of HGG and consensus-reviewed diagnoses led us to perform further survival analyses for both groups. We compared the two groups of patients for biological markers, and evaluated the neuropsychological and QOL outcomes of long-term survivors. Patients <3 years (n = 49, 19.5% of all enrolled patients) at diagnosis had a 10-year EFS and OS of 29 ± 6.5% and 37.5 ± 7%, respectively, while for patients 3-6 years (n = 34, 13.5% of all enrolled patients) 10-year EFS and OS were 35 ± 8% and 36 ± 8%, respectively. Molecular marker analysis showed that a smaller proportion of patients <3 years harbored TP53 mutations (P = 0.05). Analysis of QOL outcomes with a median length of follow-up of 15.1 years (9.5-19.2) showed comparable results. QOL and survival data were similar for the two groups. A larger prospective study is justified to study the efficacy of chemotherapy only regimens in younger children.

Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group

The Children's Oncology Group's A5971 trial examined central nervous system (CNS) prophylaxis and early intensification in paediatric patients diagnosed with CNS-negative Stage III and IV lymphoblastic lymphoma. Using a 2 × 2 factorial design, the study randomized patients to Children's Cancer Group (CCG) modified Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukaemia (ALL) regimen with intensified intrathecal (IT) methotrexate (MTX) (Arm A1) or an adapted non-Hodgkin lymphoma/BFM-95 therapy with high dose MTX in interim maintenance but no IT-MTX in maintenance (Arm B1). Each cohort was randomized ± intensification (cyclophosphamide/anthracycline) (Arms A2/B2). For the 254 randomized patients, there was no difference in 5-year event-free survival (EFS) for the four arms: Arm A1, 80% [95% confidence interval (CI) 67-89%] and Arm A2, 81% (95% CI 69-89%); Arm B1, 80% (95% CI 68-88%) and Arm B2, 84% (95% CI 72-91%). The cumulative incidence of CNS relapse was 1·2%. Age <10 years and institutional imaging response at 2 weeks was associated with improved outcomes (P < 0·001 and P = 0·014 for overall survival). CNS positive patients (n = 12) did poorly [5-year EFS of 63% (95% CI 29-85%)]. For CNS-negative patients, there was no difference in outcome based on CNS prophylaxis (IT-MTX versus HD-MTX) or with intensification.

Targeted Immunotherapy for High-Risk Neuroblastoma—The Role of Monoclonal Antibodies

To systematically review clinical trials evaluating anti-disialoganglioside (GD2) antibodies in treating high-risk neuroblastoma in children. A literature search was conducted in PubMed/MEDLINE, International Pharmaceutical Abstracts, and Cumulative Index of Nursing and Allied Health Literature (all searches 1990-August 2012) using the terms neuroblastoma, immunotherapy, 3F8, ch14.18, and hu14.18. Meeting abstracts presented between 1990 and 2012 from the American Society of Clinical Oncology, European Society for Medical Oncology, the American Society of Pediatric Hematology Oncology, Society of Surgical Oncology, and the American Society of Hematology were also evaluated. All completed and ongoing clinical trials of anti-GD2 antibodies in neuroblastoma were included. References from selected articles were also reviewed to identify additional citations. In 1999, the results of a Children's Cancer Group trial established that consolidation therapy after induction, surgery, and radiation should include purged autologous stem cell rescue followed by maintenance with isotretinoin. Overall survival at 7 years with this regimen remains below 30%. Over the following decade, antibodies targeting GD2, a surface antigen found on the surface of neuroblastoma cells, have emerged as a major therapeutic development for high-risk neuroblastoma. Anti-GD2 antibodies incite immune-mediated cytotoxicity toward neuroblastoma cells when given as monotherapy or in combination with cytokines such as sargramostim (granulocyte-macrophage colony-stimulating factor) or aldesleukin (interleukin-2). Responses to anti-GD2 agents appear most notable in patients with minimal residual disease following standard therapy. A chimeric preparation, ch14.18, is the only anti-GD2 antibody to be evaluated in a large controlled clinical trial, in which it demonstrated overall survival of 86% at 2 years in patients with high-risk neuroblastoma. Older nonrandomized studies of ch14.18 monotherapy and 3F8, a murine antibody, suggest this survival rate remains between 50 and 85% at 5 years posttreatment. Multiple GD2-specific monoclonal antibodies have been researched over the last decade in patients diagnosed with high-risk neuroblastoma. One anti-GD2 antibody, ch14.18, was found to significantly improve event-free and overall survival of high-risk neuroblastoma. Therefore, the standard approach to treating high-risk neuroblastoma is likely to undergo a major shift once an anti-GD2 antibody becomes commercially available.