Children's Oncology Group Institutions Research Articles

Role of non-chromosomal birth defects on the risk of developing childhood Hodgkin lymphoma: A Children's Oncology Group study.

Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. Information on cases (n=517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n=784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26). Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those<15 years of age, we did not observe strong associations between being born with a birth defect and HL risk.

Delivery of Care for Pediatric Patients Receiving Blinatumomab: A Children's Oncology Group Study.

Blinatumomab is an immunotherapy agent used in pediatric oncology for the treatment of B-lineage acute lymphoblastic leukemia. Administration of blinatumomab, via continuous 28-day infusion cycles, can present multiple decision points and challenges related to patient care. Nurses are at the forefront of coordinating and delivering care for patients receiving blinatumomab. To describe the current state of practice across Children's Oncology Group (COG) member institutions regarding blinatumomab administration in both inpatient and home/outpatient settings. Between August and December 2021, a cross-sectional survey was used to determine current institutional practices related to blinatumomab administration. A single targeted respondent who was actively engaged in coordinating blinatumomab administration completed the survey on behalf of each COG institution. Survey participation rate was 78% (150/192). During the first 28-day blinatumomab cycle, 71 institutions (53%) reported patient hospital stays between 73 hours and 7 days; 42 (31%) reported hospital stays ≤72 hours, and only 12 (9%) reported hospitalization for the full 28-day infusion. Small- to medium-size institutions were more likely to report longer hospitalizations (P = .03). Most blinatumomab administration occurred in the outpatient setting, with low rates of unplanned clinic/emergency room visits. The majority of COG institutions have navigated the complex coordination of care required for children to receive blinatumomab at home. Wide variations in practice were noted across institutions. This study describes current institutional practices surrounding administration of 28-day blinatumomab infusions in children with leukemia and offers a starting point for institutional benchmarking and standardization of practice.

VMAT TBI Technique Using Autoplanning Scripts

Evident by the Children's Oncology Group (COG) survey of pediatric total body irradiation (TBI) practice, 100% of physicians were open to refining the conventional TBI technique to lower the lung dose and 75% of respondents were interested in implementing VMAT or a 3-D CRT and IMRT system TBI. Unfortunately, only a handful of COG institutions have implemented VMAT or Tomo TBI. We created the autoplanning scripts and shared them with the public to make the VMAT TBI more wide-spread. Here, we report on our initial experience of treating Stanford VMAT TBI technique using the scripts. From October 2019 to February 2023, 75 patients were treated with VMAT TBI at our institution. Organ sparing depended on the regimen: myeloablative (lungs, kidneys, and lenses); non-myeloablative (lungs, kidneys, lenses, gonads, brain, and thyroid). Treatment planning was performed using Eclipse Scripting Application Programming Interface (ESAPI) auto-planning scripts. Data on patient, treatment details, and dosimetric indices were collected. Treatment was delivered using IGRT for every isocenter and every fraction. In-vivo measurements were performed on the matchline between the VMAT and AP/PA fields and on the testes for the first fraction. Median patient age was 13 years (range, 1 - 64). The patient height and width range were 83.6-197.3 cm and 24.9-60.3 cm, respectively. Forty-eight percent of patients were treated using myeloablative and 52% nonmyeloablative regimens. For all patients the lungs, lungs-1cm, and kidneys Dmean were consistently spared to 59.8±4.7%, 43.0±6.5%, and 70.9±7.7% of the prescription dose, respectively. Gonadal sparing (Dmean = 31.5±5.9%) was achieved for all patients with benign disease. In addition, brain and thyroid was spared for these patients. For nine patients, VMAT TBI offered additional organ sparing (liver, heart, and previously irradiated areas) and possibility to perform the simultaneously integrated boost. The average PTV D1cc was 120.3±6.6% for all patients. PTV D1cc correlated with patient height and width (R2 = 0.62 and 0.53). Sixteen patients (21.3%) with height <116cm were treated with 3-isocenter VMAT only plans, 59 patients (78.6%) were treated with 3-4 isocenter VMAT plans in head-first-supine position and 1-3 AP/PA plan in feet-first-supine position. Rotational platform was used to change the patient orientation. The average matchline dose measurement indicated patient setup was reproducible (96.1±4.5% relative to planned dose). For the first 35 patients, treatment time, including patient setup and beam-on, was 47.5±9.5 min. VMAT TBI is a modern alternative to conventional 2D TBI treatment offering the possibility of organ sparing, dose painting, and accurate treatment using IGRT. The automated scripts enable streamline planning with consistent plan quality.

Fertility Preservation Practices at Pediatric Oncology Institutions in the United States: A Report From the Children's Oncology Group.

Fertility discussions are an integral part of comprehensive care for pediatric, adolescent, and young adult patients newly diagnosed with cancer and are supported by national guidelines. Current institutional practices are poorly understood. A cross-sectional survey was distributed to 220 Children's Oncology Group member institutions regarding fertility discussion practices. Descriptive statistics were calculated for all variables. The association between specific practices and selected outcomes on the basis of sex was examined via multivariable logistic regression. One hundred forty-four programs (65.5%) returned surveys. Of these, 65 (45.1%) reported routine discussions of fertility with all female patients and 55 (38.5%) all male patients (P = .25). Ninety-two (63.8%) reported no specific criteria for offering females fertility preservation (FP), compared with 40 (27.7%) for males (P < .001). Program characteristics associated with fertility discussions included reproductive endocrinology and infertility on site (females odds ratio [OR], 2.1; 95% CI, 1.0 to 4.3), discussion documentation mandate (females OR, 2.3; 95% CI, 1.0 to 5.5; males OR, 3.5; 95% CI, 1.4 to 8.7), and cumulative institution-based FP infrastructure (which included [1] routine practice of documentation, [2] template for documentation, [3] mandate for documentation, and [4] availability of FP navigation; females OR, 1.6; 95% CI, 1.1 to 2.3; males OR, 2.3; 95% CI, 1.6 to 3.4). Utilization of practices unsupported by guidelines included offering sperm banking after treatment initiation (39/135 programs; 28.9%), gonadotropin-releasing hormone analogs for ovarian suppression/FP (75/144 programs; 52.1%), ovarian tissue cryopreservation at diagnosis for patients with leukemia (19/64 programs; 29.7%), and testicular tissue cryopreservation (23/138 programs; 16.7%) not part of a clinical trial. Despite recommended guidelines, fertility discussions with patients/families before treatment initiation are not routine at Children's Oncology Group institutions. Standard criteria to determine which options should be offered to patients are more common for males than females.

Challenges and Barriers to Adverse Event Reporting in Clinical Trials: A Children's Oncology Group Report.

Adverse event (AE) reporting is crucial for determining safety of trials. Adverse events are captured manually by clinical research associates (CRAs) and research nurses (RNs), and prior studies show underreporting. It is necessary to understand AE reporting training, processes, and institution-level differences to improve AE capture. A 26-item questionnaire regarding AE reporting training, identification, tracking, and challenges was distributed to all Children's Oncology Group (COG) CRAs and RNs from February 15 to March 11, 2019, regardless of if they report AEs based on limitations of COG rosters. Results were tabulated. Institutions were grouped by self-reported full-time equivalents and compared using χ2 tests. Of 1315 CRAs and 2703 RNs surveyed, 509 (12.7%) responded. Of those, 369 (64.9%) representing 71.8% of COG institutions report AEs. Only data from respondents who report AEs were collected and analyzed. There was a range in AE training; COG training modules were most common (79.7%). There was wide variability in AE ascertainment; only 51.2% use standardized approaches at their site. There was no standard AE tracking method; larger sites more commonly use spreadsheets (P = 0.002) and smaller sites more commonly use paper (P = 0.028). The greatest AE reporting challenges were differences between protocols (70%) and between AE definitions and documentation (53%). Half of the respondents endorsed 6 of 13 proposed tools for improving reporting including online AE reporting modules (75.3%), tip sheets for interpreting Common Terminology Criteria for Adverse Events definitions (67.5%), and standardized AE tracking forms (66.9%). Only half of the respondents reported that all colleagues at their site followed the same AE reporting practices, and there was no dominant AE tracking approach across the respondents. There is wide variability in AE reporting training and practices. Numerous challenges exist, including differences between trials, challenges in interpreting AE definitions, and engaging clinicians. Respondents are eager for additional central resources. These results provide a roadmap for areas of potential improvement.

Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma

Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed. To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma. A randomized clinical phase 3 trial was conducted from March 2007 to September 2018. Analysis was completed in September 2020. Patients aged 3 to 21 years with newly diagnosed high-risk medulloblastoma from Children's Oncology Group institutions within the US, Canada, Australia, and New Zealand were included. High-risk features included metastasis, residual disease, or diffuse anaplasia. Patients were randomized to receive 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance. The primary clinical trial end point was event-free survival, using the log-rank test to compare arms. The primary biology study end point was molecular subgroup classification by DNA methylation array. Of 294 patients with medulloblastoma, 261 were evaluable after central radiologic and pathologic review; median age, 8.6 years (range, 3.3-21.2); 183 (70%) male; 189 (72%) with metastatic disease; 58 (22%) with diffuse anaplasia; and 14 (5%) with greater than 1.5-cm2 residual disease. For all participants, the 5-year event-free survival was 62.9% (95% CI, 55.6%-70.2%) and overall survival was 73.4% (95% CI, 66.7%-80.1%). Isotretinoin randomization was closed early owing to futility. Five-year event-free survival was 66.4% (95% CI, 56.4%-76.4%) with carboplatin vs 59.2% (95% CI, 48.8%-69.6%) without carboplatin (P = .11), with the effect exclusively observed in group 3 subgroup patients: 73.2% (95% CI, 56.9%-89.5%) with carboplatin vs 53.7% (95% CI, 35.3%-72.1%) without (P = .047). Five-year overall survival differed by molecular subgroup (P = .006): WNT pathway activated, 100% (95% CI, 100%-100%); SHH pathway activated, 53.6% (95% CI, 33.0%-74.2%); group 3, 73.7% (95% CI, 61.9%-85.5%); and group 4, 76.9% (95% CI, 67.3%-86.5%). In this randomized clinical trial, therapy intensification with carboplatin improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma. These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma. ClinicalTrials.gov Identifier: NCT00392327.

Pediatric oncology clinician communication about sexual health with adolescents and young adults: A report from the children's oncology group.

BackgroundSexual health (SH) is an important concern for adolescents and young adults (AYAs). This study determined current SH communication practices, barriers, and additional resources needed among pediatric oncology clinicians who treat AYAs.MethodsA cross‐sectional survey was developed by the Children's Oncology Group (COG) AYA Committee and sent to pediatric oncologists (n = 1,987; 85.9%) and advanced practice providers (APPs, n = 326; 14.1%) at 226 COG institutions. Responses were tabulated and compared using tests of proportion and trend.ResultsThe sample comprised 602 respondents from 168 institutions and was proportionally representative (468 oncologists [77.7%], 76 APPs [12.6%], 58 unidentified [9.6%]; institutional and provider response rates 74.3% and 26.2%, respectively). Almost half of respondents (41.7%) reported no/small role in SH care. Medical topics were discussed most often, including contraception (67.2%), puberty (43.5%), and sexual activity (37.5%). Topics never/rarely discussed included gender identity (64.5%), sexual orientation (53.7%), and sexual function (50.3%). Frequently cited communication barriers included lack of time, low priority, perceived patient discomfort, and the presence of a parent/guardian. Respondents endorsed the need for further education/resources on sexual function (66.1%), gender identity/sexual orientation (59.5%), and body image (46.6%). Preferred education modalities included dissemination of published guidelines (64.7%), skills training modules (62.9%), and webinars (45.3%). By provider type, responses were similar overall but differed for perception of role, barriers identified, and resources desired.ConclusionsMany pediatric oncology clinicians play minimal roles in SH care of AYAs and most SH topics are rarely discussed. Provider‐directed education/training interventions have potential for improving SH care of AYA cancer patients.

Barriers to Pediatric Oncologist Enrollment of Adolescents and Young Adults on a Cross-Network National Clinical Trials Network Supportive Care Cancer Clinical Trial.

Few studies have explored interventions to improve adolescent and young adult (AYA) cancer care delivery. While many AYAs receive cancer care at NCI Community Oncology Research Program (NCORP) sites, few enroll on clinical trials. Barriers and facilitators to pediatric oncologist activation of and enrollment on an AYA cross-network National Clinical Trials Network (NCTN) supportive care trial were assessed using a survey that was administered to 162 stakeholders representing all 47 children's oncology group (COG) institutions affiliated to an NCORP. Fifty-eight stakeholders participated representing 62% of all sites surveyed. Approximately half of participants (45%) were unaware of the trial. Seven sites had the study open and one enrolled a patient. Reasons for not opening and enrolling on the trial included limited research staff and resources, low anticipated accrual, and lower prioritization of the trial. Enrollment facilitators included having a local "AYA champion," improving communication between pediatric and medical oncology, and having site education on available AYA trials. Interventions focused on increasing site and provider awareness of AYA trials and decreasing local barriers to AYA enrollment are needed.

Evaluation of Activation of a NCI National Clinical Trials Network (NCTN) Study S1826 for Hodgkin Lymphoma (HL) at Children's Oncology Group (COG) Institutions

Background: HL is an adolescent and young adult (AYA) cancer that lacks uniform approaches across medical and pediatric oncology. Differences include risk classification, chemotherapy backbone and use of radiation therapy. Heterogeneity in institutional programs and resources for AYAs adds to the gap in understanding why outcomes for AYA HL differ. In order to expedite equitable access to novel agents for AYA patients by medical and pediatric oncology providers, a NCTN facilitated trial for advanced stage HL was launched. The SWOG-led S1826 trial (NCT03907488), open to patients &amp;gt; 12 years of age, was activated in July 2019. We assessed barriers and facilitators to trial activation at COG institutions for this first in-kind approach. Methods: A web-based survey was distributed through the COG communications office to institutional principal investigators (PIs) of 216 institutions in North America. To achieve optimal response rates, the survey was distributed in four waves over a 6-week period. Branching logic differentiated questions for institutions that had opened or planned to open the trial vs. those who did not. Topics included institutional characteristics, joint partnership with medical oncologists to activate AYA trials, and specific barriers for opening this trial. Descriptive statistics were calculated using SAS v.7.1. Results: The response rate was 73% with 158 unique responses among 216 COG institutions queried. Among responding institutions 24% were freestanding children's hospitals; 18% were NCI-designated cancer centers. 55% of respondents indicated a known affiliation with another NCTN cooperative group other than COG. 31% indicated prior experience in participating in a non-COG led NCTN trial for other diseases. 42% of institutions reported a central trials infrastructure for joint pediatric and medical oncology trials. 44% indicated use of the central IRB mechanism, and 4% used a provincial IRB. While 40% had an established AYA oncology program, 30% reported regular lymphoma tumor boards with medical oncology; 8% indicated the ability to see AYA lymphoma patients in a joint pediatric and medical oncology clinic. The trial is open at 79/158 (50%) COG institutions to date and an additional 56 indicated future intent to open the trial. Among 135 COG institutions with open or intent-to-open status, 73% of institutional principal investigator (PI) were pediatric oncologists, 24% were medical oncologists and 4% were joint PIs. PI determination was based on: enrolling as a COG-only site (57%); institutional policy (5%); a discussion among investigators (23%); or other factors (14%). These were categorized as: more resources or anticipated patients in medical oncology (n=4); the trial being opened in medical oncology before pediatrics (n=11); being open in pediatrics before medical oncology (n=2); no interface for joint studies (n=1). Among the 14% of respondents who indicated the trial would not be opened, a competing trial was the reason in 35%. Other reasons included: lack of awareness of the trial, concerns about study design or chemotherapy backbone, lack of easily accessible protocol documents, anticipated lack of accrual, concerns around funding support, challenges with regulatory support, data management, or institutional process for medical and pediatric joint trials. Respondents' recommendations for facilitating activation of AYA intergroup studies include needs for: increased resources and funding; guidance on communication and navigation with medical oncologists for managing joint trials; institutional infrastructure for AYA trials; clearer rationale for a change in the chemotherapy backbone relative to prior COG studies; accessibility and consistency of protocol study naming conventions and protocol documents (i.e. therapy roadmap) on the COG electronic site. Conclusions: Successful implementation of AYA trials is germane to early access to novel agents for younger adolescents. Overall, COG institutions indicate a high level of endorsement for a NCTN AYA trial for HL with 85% indicating activation completed or planned. This survey suggests that AYA trials can be implemented successfully in a network but require education, early communication between pediatric and medical oncologists, and flexible infrastructure for all group participants. (Funding: U10CA180886, U10CA180888, and UG1CA233230) Disclosures Parsons: Seattle Genetics: Consultancy. Herrera:Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Karyopharm: Consultancy; Pharmacyclics: Research Funding. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Astellas: Consultancy; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy; Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Portola Pharmaceuticals: Consultancy.

Assessment of provider perspectives on otoprotection research for children and adolescents: A Children's Oncology Group Cancer Control and Supportive Care Committee survey.

Cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity for childhood cancer survivors. Understanding provider perspectives is crucial to developing otoprotection studies that are both informative and feasible. Two international trials (ACCL0431 and SIOPEL6) investigated the drug sodium thiosulfate (STS) as an otoprotectant, but definitive interpretation of the findings of these trials has been challenging. Adoption of STS has therefore been uneven, and provider perspectives on its role are unknown. The Children's Oncology Group (COG) Cancer Control and Supportive Care Neurotoxicity Subcommittee therefore conducted a survey of providers at COG institutions to determine perspectives on pediatric otoprotection practices and research surrounding three major themes: (1) prevalence of routine use of STS with cisplatin-based regimens, (2) application of audiometry to cisplatin therapy, and (3) preferred modalities for otoprotection research. Survey respondents (45%, 44/98 surveyed institutions) were of diverse institutional sizes, practice settings, and geographical locations primarily in the United States and Canada. Overall, respondents considered CIHL an important toxicity and indicated strong enthusiasm for future studies (98%, 40/41). Results indicated that while STS was the current or planned standard of care in a minority of responding institutions (36%, 16/44), most sites were receptive to its inclusion in appropriate study designs. Application of audiometry for ototoxicity monitoring varied widely across sites. For otoprotection research, systemic agents were preferred (68%, 28/41) as compared with intratympanic approaches. These results suggest that pediatric otoprotection trials remain of interest to providers; the emphasis of these trials should remain on systemic and not intratympanic therapy.

Pediatric oncology provider perspectives and practices: Supporting patients and families in schooling after cancer diagnosis.

Cognitive limitations are common after childhood cancer and require assessment and support in the medical and school setting. Pediatric oncology providers are tasked with educating families about the side effects of disease/treatment, and supporting families as they navigate the associated challenges. Despite this important role, little is known about the training, practice, and knowledge of providers in the domain of cognitive/school impacts. An online survey was emailed to Children's Oncology Group (COG) member physicians in the United States. The survey consisted of 42 questions about training and practice, and 4 knowledge questions about neurocognitive impacts and school supports. Surveys were completed by 282 physicians representing 64% of COG institutions and a diverse group of experience and institution size. The pediatric oncologist was reported most frequently (93%) as the person at their institution to provide information to families on this topic, yet 54% reported receiving no specific training in this area and the majority (66%) reported to only "somewhat" understand the issues pediatric oncology patients face when returning to school. A minority reported available institutional guidelines (42%) or screening tools (19%) to assist in making referrals or assessments. Knowledge questions concerning health conditions qualifying children for school supports received the fewest correct answers. The majority (77%) thought more training would be helpful. Additional training about cognitive impacts and schooling challenges associated with childhood cancer is needed to prepare providers to support parents/children. In addition, establishing policy guidelines and screening procedures may help support providers in providing care.

Factors related to lymph node sampling at the time of surgery in children, adolescents, and young adults with unilateral non-metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is rare in the pediatric, adolescent, and young adult (PAYA) population. PAYA patients with RCC have a high rate of lymph node (LN) involvement, regardless of primary tumor size, yet data to guide surgical LN management in this group are limited. The objective of this study was to determine what factors are associated with LN sampling (protocol adherence) in PAYAs with RCC. The National Cancer Database (NCDB) between 2004 and 2013 was queried for patients aged ≤30yrs with non-metastatic, unilateral RCC managed with surgery. Logistic regression analyses were performed to evaluate factors associated with LN sampling. A total of 2857 patients met study criteria. Pathologically, 2510 (87.8%) patients were Nx, 278 (9.7%) N0, and 69 (2.4%) N1. Older age was associated with omission of LN sampling (odds ration [OR]: 1.065, 95% confidence interval [CI]: 1.04-1.1, P<0.001). Higher institutional volume (OR: 0.971, 95% CI: 0.96-0.99, P<0.001), stage 3 tumors (OR: 0.19, 95% CI: 0.11-0.33, P<0.001), pre-operative clinical node involvement (OR: 0.32, 95% CI: 0.12-0.86, P=0.024), tumor size >10cm (OR: 0.27, 95% CI: 0.12-0.57, P=0.001), and radical nephrectomy (OR: 0.245, 95% CI: 0.16-0.38, P<0.001) were associated with patients undergoing LN sampling. Lymph node sampling is performed in <15% of PAYA patients with RCC. Given the higher rate of translocation RCC pathology in younger patients, which leads to a higher prevalence of nodal involvement (especially with small masses), and the subsequent need for aggressive surgical control of disease, LN sampling and protocol adherence are potentially underutilized in this population and may present a unique opportunity for urologists to improve the care of PAYAs. Data from administrative databases are helpful for rare diseases such as PAYA RCC, but comes with limitations such as missing data. There are several factors that could contribute to LN sampling utilization (National comprehensive cancer network (NCCN) or Children's Oncology Group institution designation, surgeon experience, annual volume, specialty, operative approach, etc.) that cannot be further examined using the NCDB. Pediatric, adolescent, and young adult patients with localized RCC are less likely to undergo surgical LN sampling if they are older, have tumors <10cm or of less advanced stage, have no pre-operative clinical suspicion of LN involvement, are treated with partial nephrectomy, or are treated at lower volume centers. It appears that approaches from adults with RCC are being applied to PAYAs despite evidence that PAYAs with RCC experience a significant rate of LN involvement even with small tumors.

Cesarean Delivery and Risk of Infant Leukemia: A Report from the Children's Oncology Group.

Background: Studies have reported increased risks of pediatric acute lymphoblastic leukemia (ALL) among children born by cesarean delivery (CD). However, no previous study has examined the impact of CD on risk of infant leukemia specifically.Methods: In this study, 443 infants diagnosed with acute leukemia, including both ALL and acute myelogenous leukemia (AML), were identified at Children's Oncology Group institutions between January 1996 and December 2006; 324 controls frequency matched by year of birth were identified though random digit dialing and random selection from U.S. birth registries. Using interview data and, for a subset of participants, medical record data, we analyzed CD overall and by indications that likely resulted in pre-labor CD (PLCD) or emergency CD (ECD). Odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ALL and AML were estimated using multivariable unconditional logistic regression models, adjusted for year of birth, birth weight, and maternal race.Results: We observed an increased point estimate for the association between CD and ALL (OR, 1.52 and 95% CI, 1.02-2.25). We did not observe an association between CD and AML (OR, 1.02 and 95% CI, 0.64-1.62). In analyses of indication for CD, we observed elevated effect estimates for the associations of both PLCD and ECD and infant ALL.Conclusions: Our analysis suggests an increased risk of infant ALL following CD, including both PLCD and ECD. Altered microbiota colonization may be involved in development of leukemia in infants, but clear biological mechanisms have yet to be determined.Impact: This study provides the first in-depth examination of CD and infant leukemia. Cancer Epidemiol Biomarkers Prev; 27(4); 473-8. ©2018 AACR.

Geographic Access to Cancer Care and Mortality Among Adolescents.

Adolescents with cancer have had less improvement in survival than other populations in the United States. This may be due, in part, to adolescents not receiving treatment at Children's Oncology Group (COG) institutions, which have been shown to increase survival for some cancers. The objective of this ecologic study was to examine geographic distance to COG institutions and adolescent cancer mortality. We calculated cancer mortality among adolescents and sociodemographic and healthcare access factors in four geographic zones at selected distances surrounding COG facilities: Zone A (area within 10 miles of any COG institution), Zones B and C (concentric rings with distances from a COG institution of >10-25 miles and >25-50 miles, respectively), and Zone D (area outside of 50 miles). The adolescent cancer death rate was highest in Zone A at 3.21 deaths/100,000, followed by Zone B at 3.05 deaths/100,000, Zone C at 2.94 deaths/100,000, and Zone D at 2.88 deaths/100,000. The United States-wide death rate for whites without Hispanic ethnicity, blacks without Hispanic ethnicity, and persons with Hispanic ethnicity was 2.96 deaths/100,000, 3.10 deaths/100,000, and 3.26 deaths/100,000, respectively. Zone A had high levels of poverty (15%), no health insurance coverage (16%), and no vehicle access (16%). Geographic access to COG institutions, as measured by distance alone, played no evident role in death rate differences across zones. Among adolescents, socioeconomic factors, such as poverty and health insurance coverage, may have a greater impact on cancer mortality than geographic distance to COG institution.

Adolescent and Young Adult Oncology Patients with Acute Lymphoblastic Leukemia: Shifting Location of Care over Time

BackgroundOver the past decade, research has demonstrated superior outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) when they are treated on pediatric versus adult ALL protocols, which occurs more frequently at academic centers. We hypothesized that this knowledge resulted in a greater proportion of younger adults with ALL receiving treatment at National Cancer Institute (NCI)/Children's Oncology Group (COG) designated centers over the past decade, and that an increased proportion of younger AYAs (ages 18-21) received care at pediatric (COG) versus adult centers.MethodsWe used the Office of Statewide Health Planning and Development patient discharge database to conduct a retrospective analysis of AYA patients with ALL, ages 18 to 25 and diagnosed and treated in California from 2004 to 2013. The primary outcome was receiving care at a NCI/COG designated center up to 5 years after diagnosis. Multivariable logistic regression was used to determine socio-demographic factors associated with AYAs ever receiving care from an NCI/COG designated center. Descriptive analyses were used to evaluate changes in the percentage of admissions from NCI and COG designated centers over time using a chi-square test to make comparison of proportions over time.ResultsThere were 703 patients, ages 18-25 years (52.5%, 18-21; 47.5%, 22-25 years) who were newly diagnosed with ALL and hospitalized in California between 2004 and 2013. Sixty-five percent were male and 51% had private insurance. Of these patients, 37% always received care at an NCI/COG center, while 28% sometimes and 35% never received care at these centers. Younger AYAs (18-21 years) had a higher odds of ever being discharged from a NCI/COG center (OR 1.52, CI 1.10-2.10), while AYAs living farther from a NCI/COG center were less likely to receive care at these centers (OR 0.45, CI 0.27-0.76 for 10-20 vs 0-5 miles). Over the past decade, there was an increase in the percentage of admissions to NCI/COG centers among 18-21 year-olds (53% in 2004 to 72% in 2013; p<0.001), whereas there was no significant increase for 22-25 year-olds (44% in 2004 to 49% in 2013; p=0.435) (Figure). When admissions to an NCI and COG center were considered separately, differences were observed by age group. There was a lower percentage of admissions to NCI centers over time in 18-21 year-olds (34% in 2004 to 27% in 2013; p=0.183), but a significant increase in admissions to NCI centers in 22-25 year-olds (27% in 2004 to 40% in 2013; p=0.035). Alternatively, there was a significant increase in the percentage of admissions to COG centers in the 18-21 year-olds (48% to 67%; p<0.001), with a somewhat smaller increase in admissions to COG centers in 22-25 year-olds (25% to 32%; p=0.278) from 2004 to 2013.ConclusionsOver the past decade, approximately 37% of younger (18-25 years) AYAs with ALL always received care at NCI/COG designated centers, with younger age and shorter geographical distance to a NCI/COG designated center being the main predictors for receiving care at these centers. Over the study period, the percentage of admissions increased at NCI centers for 22-25 year-olds and COG centers for 18-21 year-olds. These findings support our hypothesis that there has been a shift in treatment of younger AYAs (18-21 years) to COG designated centers over the past decade. Further research is warranted to determine the roles that referral patterns, insurance networks, patient preference and other barriers play in receiving care at NCI and/or COG institutions and the effect of care at these centers on survival in population-based data. [Display omitted] DisclosuresWun:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi: Research Funding.

Effect of Dexrazoxane on Heart Function Among Long-Term Survivors of Childhood Leukemia and Lymphoma: A Report from the Children's Oncology Group (COG)

Background:Dexrazoxane (DRZ) has been shown to have cardioprotective effects among doxorubicin-treated childhood cancer survivors up to 5-years after therapy completion, including effects on fractional shortening (FS%) and other parameters of left ventricular anatomy and function. However, data on longer-term effects are lacking.Methods: COG protocols P9404 (T-cell acute lymphoblastic leukemia/lymphoma; cumulative doxorubicin 360 mg/m2), P9425 (advanced stage Hodgkin lymphoma; cumulative doxorubicin 180-300 mg/m2), and P9426 (low/intermediate stage Hodgkin; cumulative doxorubicin 100-200 mg/m2) were phase 3 randomized clinical trials conducted between 1996 and 2001. Patients were randomly assigned to treatment with or without DRZ (10:1 mg dose ratio of DRZ:doxorubicin); DRZ was given as an intravenous bolus before each doxorubicin dose. Beginning in 2014, a subset of COG institutions began prospectively reassessing the cardiovascular health of long-term survivors in first complete remission treated on these 3 protocols, including echocardiography and selected blood biomarkers (e.g., high-sensitivity troponins, b-type natriuretic peptides [BNP], N-terminal [NT] proBNP). Echocardiograms and blood analytes were all processed centrally, with DRZ status masked.Results: To date, 94 participants (54% DRZ+; 57% male; average doxorubicin dose 279 mg/m2; current mean age 28 years and 16 years since cancer diagnosis) have been recruited from 30 institutions. Participants were similar with respect to demographic and treatment characteristics when compared by DRZ status. Overall, compared with DRZ+ participants, DRZ- participants had non-significantly reduced FS% (mean±SD: 33.0±4.8 vs. 34.8±4.6; p=0.10), but greater myocardial wall stress and dysfunction as measured by BNP (mean±SD: 18.3±14.7 vs. 11.3±10.6 pg/mL; p=0.02) and NT-proBNP (64.8±55.5 vs. 44.5±39.0 pg/mL; p=0.06). When the analysis was restricted to those who received the greatest doxorubicin exposure (P9404 participants, n=41), differences all became statistically significant (FS%: 31.3±3.9 vs. 34.9±3.7, p<0.01; BNP and NT-proBNP: p=0.03 for both). Only a subset of participants (n=43) had ejection fraction evaluable, but DRZ+ patients also were more likely to have greater values (mean±SD: 56.8±6.3 vs. 61.2±6.4; p=0.03). Among all participants, the effects of DRZ on FS% appeared to vary by sex, with females showing significant differences (DRZ- 31.7±2.2 vs. DRZ+ 36.3±4.2; p<0.001) but not males (DRZ- 34.0±6.0 vs. DRZ+ 34.0±4.6; p=0.99). DRZ status was significantly associated with FS% and both BNP and NT-proBNP in multivariate analyses that adjusted for sex, original protocol, race/ethnicity, current age, and age at cancer diagnosis (p<0.05). Other parameters of systolic dysfunction and myocardial injury including wall thickness/dimension ratio and high-sensitivity troponins were similar across study arms, both overall and in subanalyses. Overall, only 3 participants had FS% <28 (DRZ+, n=2). Two other participants reported a history of clinical cardiomyopathy (both DRZ+, one currently on medications). Globally, regardless of DRZ status, participants had a high burden of comorbid cardiovascular conditions: 57% overweight/obese, 37% pre-/hypertensive, 50% with dyslipidemia, and 11% pre-/diabetic.Conclusion: In this preliminary analysis, long-term survivors of childhood cancer treated with doxorubicin and DRZ appeared to have more preserved systolic function and reduced myocardial wall stress compared with survivors treated with doxorubicin alone. Secondary prevention efforts should be directed at treating common but potentially modifiable cardiovascular risk factors in this high-risk young adult population. Accrual of remaining eligible study participants is ongoing and may provide more refined estimates of DRZ's cardioprotective effects in the future. DisclosuresAsselin:Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Lipshultz:Clinigen Group: Consultancy, Other: Travel/accommodations for consulting related meeting; Pfizer: Research Funding; Roche Diagnostics: Research Funding.

A Comprehensive Survey of Institutional Patient/Family Educational Practices for Newly Diagnosed Pediatric Oncology Patients.

Patient/family education is an important component of nursing practice and is essential to the care of children newly diagnosed with cancer. Practices regarding patient/family education in Children's Oncology Group (COG) treatment centers have not been well described. We used an Internet-based survey to determine current patient/family educational practices at COG institutions; participation rate was 90.5% (201/222). Patient/family education was delivered primarily by an individual (rather than a team) at 43% of institutions. Advanced practice nurses had primary responsibility for providing education at 32% of institutions. "Fever" was the most frequently reported topic considered mandatory for inclusion in education for newly diagnosed patients. More than half of institutions reported using checklists and/or end-of-shift reports to facilitate health care team communication regarding patient/family education, and 77% reported using the "teach-back" method of assessing readiness for discharge. Thirty-seven percent of institutions reported delays in hospital discharge secondary to the need for additional teaching. An understanding of current practices related to patient/family education is the first step in establishing effective interventions to improve and standardize educational practices in pediatric oncology.

Low Enrollment of Adolescents and Young Adults Onto Cancer Trials: Insights From the Community Clinical Oncology Program.

Stagnant outcomes for adolescents and young adults (AYAs; 15 to 39 years old) with cancer are partly attributed to poor enrollment onto clinical trials. The National Cancer Institute (NCI) Community Clinical Oncology Program (CCOP) was developed to improve clinical trial participation in the community setting, where AYAs are most often treated. Further, many CCOP sites had pediatric and medical oncologists with collaborative potential for AYA recruitment and care. For these reasons, we hypothesized that CCOP sites enrolled proportionately more AYAs than non-CCOP sites onto Children's Oncology Group (COG) trials. For the 10-year period 2004 through 2013, the NCI Division of Cancer Prevention database was queried to evaluate enrollments into relevant COG studies. The proportional enrollment of AYAs at CCOP and non-CCOP sites was compared and the change in AYA enrollment patterns assessed. All sites were COG member institutions. Although CCOP sites enrolled a higher proportion of patients in cancer control studies than non-CCOP sites (3.5% v 1.8%; P < .001), they enrolled a lower proportion of AYAs (24.1% v 28.2%, respectively; P < .001). Proportional AYA enrollment at CCOP sites decreased during the intervals 2004 through 2008 and 2009 through 2013 (26.7% v 21.7%; P < .001). Despite oncology practice settings that might be expected to achieve otherwise, CCOP sites did not enroll a larger proportion of AYAs in clinical trials than traditional COG institutions. Our findings suggest that the CCOP (now the NCI Community Oncology Research Program) can be leveraged for developing targeted interventions for overcoming AYA enrollment barriers.

Abstract A37: De novo and transmitted germline TP53 variation in pediatric osteosarcoma: A report from the Children's Oncology Group

Abstract Pathogenic germline variation in TP53, usually accompanied by familial Li-Fraumeni syndrome (LFS), is known to underly a small proportion of pediatric osteosarcoma (OS). However, the extent to which de novo mutations and rare but mildly deleterious variation in TP53 are found in the genomes of OS patients is only now coming into focus with next-generation sequencing. We recruited 285 patients with OS diagnosed at &amp;lt;20 years of age from North American Children's Oncology Group institutions between December, 2007 and March, 2010. Oragene saliva collection kits (DNA Genotek, Ottawa, Canada) or buccal swabs for DNA extraction were collected from patients and their parents, resulting in 229 complete triads and 59 dyads. From these, 95 triads were selected for whole exome sequencing (WES) based on the availability of both patient and parent samples and sufficient DNA mass. Libraries were created using the Agilent SureSelect All Exon V5+UTRs kit and were sequenced using a HiSeq 2000 that generated 100bp paired end reads with an average insert size of 188.8bp. We implemented the best practices as delineated in the GATK pipeline, including using BWA-MEM for alignment, GATK for quality recalibration and indel realignment, and GATK HaplotypeCaller for genotyping. On average, 35.0 million reads were delivered per sample, and the average read depth was 36.4x coverage. The average proportion of TP53 exons covered at 20x coverage was 76.2% (compared to 78.7% for all genes). Exons 1 and 9 were the only exons with poor coverage (mean coverage &amp;lt;20x). All putative TP53 variants were verified via Sanger sequencing; only verified variants are reported hereafter. Sequence variants were annotated using SNPEFF and ANNOVAR. Five patients exhibited rare, synonymous variation in exons 4 (Pro36Pro, 2 patients) and 6 (Arg213Arg, 3 patients). One patient exhibited rare, non-synonymous variation in exon 4 (Pro47Ser); this variant has a frequency of 0.005 across all populations in 1000 Genomes data and was predicted to be deleterious in 2 of 8 functional prediction algorithms. An additional two patients exhibited rare, non-synonymous variation in exons 7 (Cys238Tyr) and 8 (Gly279Glu). Neither variant was detected in parents or reported in 1000 Genomes data, and both were predicted to be deleterious by all functional prediction algorithms. The prevalence of pathogenic TP53 variation in our data (3/95 or 3.2%) is roughly similar to that reported previously, but importantly 2 of the 3 rare, non-synonymous variants were de novo. These results underscore the contribution of new mutations to OS risk and suggest that genetic counseling and TP53 mutation testing should be offered to patients even in the absence of a family history suggestive of LFS. This research was funded by NIH R01CA122371 and grants from the Hyundai Hope on Wheels foundation and the Zach Sobiech Osteosarcoma Fund of the Children's Cancer Research Fund, Minneapolis, MN. Citation Format: Logan Spector, Ian Lock, John Lane, Aaron Sarver, Mark Krailo, Rajaram Nagarajan, Nathan Pankratz. De novo and transmitted germline TP53 variation in pediatric osteosarcoma: A report from the Children's Oncology Group. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A37.

Chemotherapy-Induced Nausea and Vomiting Prophylaxis: Practice Within the Children's Oncology Group

The Children's Oncology Group (COG) has endorsed a clinical practice guideline (CPG) for acute chemotherapy-induced nausea and vomiting (CINV) prophylaxis in children with cancer. This project aims to describe current acute CINV prophylaxis practice at COG sites and the gap between this practice and CPG recommendations. Two surveys were developed. The first survey, sent to 94 cancer control and supportive care responsible individuals (CCL RIs) at 94 COG institutions, asked if the institution had a standardized approach to practice and focused on antiemetic agent choice. The second survey, sent to 54 pharmacists at COG sites where the CCL RI indicated that there was a standardized approach to CINV prophylaxis practice, focused on antiemetic dosing. Survey results were described and analyzed for consistency with the CPG recommendations. Among the 69 respondents to the first survey, 54 (78%) stated that their institutions have a standardized approach to CINV prophylaxis practice. However, antiemetic choice varied widely among respondents. Results from the 36 respondents to the second survey also demonstrated significant antiemetic dosing practice variability. Frequent sources of deviation from CPG recommendations were as follows: antiemetic choice when corticosteroids are contraindicated, dexamethasone dosing, aprepitant use in children less than 12 years, and aprepitant use in the presence of a known or suspected drug interaction. There is a great diversity in the CINV prophylaxis provided to children with cancer at COG sites. Concerted strategies are required to improve awareness of the current CINV prophylaxis CPG and to facilitate CPG-consistent CINV prophylaxis.