\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Children's Oncology Group's 2023 Blueprint for Research: Behavioral
Science}



\author[1]{Leanne Embry}%
\author[2]{Kristin Bingen}%
\author[3]{Heather Conklin}%
\author[4]{Steven Hardy}%
\author[3]{Lisa Jacola}%
\author[5]{Jordan Marchak}%
\author[6]{Iris Paltin}%
\author[7]{Wendy Pelletier}%
\author[8]{Katie Devine}%
\affil[1]{The University of Texas Health Science Center at San Antonio Department of Pediatrics}%
\affil[2]{Medical College of Wisconsin Department of Pediatrics}%
\affil[3]{St Jude Children’s Research Hospital}%
\affil[4]{The George Washington University School of Medicine and Health Sciences}%
\affil[5]{Children's Healthcare of Atlanta Inc Aflac Cancer and Blood Disorders Center}%
\affil[6]{The Children's Hospital of Philadelphia Department of Child and Adolescent Psychiatry and Behavioral Sciences}%
\affil[7]{University of Calgary Department of Oncology}%
\affil[8]{Rutgers Cancer Institute of New Jersey}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
As survival rates for childhood cancer have improved, there has been
increasing focus on identifying and addressing adverse impacts of cancer
and its treatment on children and their families during treatment and
into survivorship. The Behavioral Science Committee (BSC) of the
Children's Oncology Group (COG), comprised of psychologists,
neuropsychologists, social workers, nurses, physicians, and clinical
research associates, aims to improve the lives of children with cancer
and their families through research and dissemination of empirically
supported knowledge. Key achievements of the BSC include enhanced
interprofessional collaboration through integration of liaisons into
other key committees within COG, successful measurement of critical
neurocognitive outcomes through standardized neurocognitive assessment
strategies, contributions to evidence-based guidelines, and optimization
of patient-reported outcome measurement. The collection of
neurocognitive and behavioral data continues to be an essential function
of the BSC, in the context of therapeutic trials that are modifying
treatments to maximize event-free survival, minimize adverse outcomes,
and optimize quality of life. In addition, through hypothesis-driven
research and multi-disciplinary collaborations, the BSC will also begin
to prioritize initiatives to expand the systematic collection of
predictive factors (e.g., social determinants of health) and
psychosocial outcomes, with overarching goals of addressing health
inequities in cancer care and outcomes, and promoting evidence-based
interventions to improve outcomes for all children, adolescents, and
young adults with cancer.%
\end{abstract}%



\sloppy


\textbf{Children's Oncology Group's 2023 Blueprint for Research:
Behavioral Science}

Leanne Embry, PhD, Department of Pediatrics, University of Texas Health
Science Center at San Antonio, San Antonio, Texas

Kristin Bingen, PhD, Department of Pediatrics, Medical College of
Wisconsin, Milwaukee, WI

Heather M. Conklin, PhD, Department of Psychology and Biobehavioral
Sciences, St. Jude Children's Research Hospital, Memphis, TN

Steven Hardy, PhD, Division of Oncology, Children's National Hospital
and Departments of Pediatrics and Psychiatry \& Behavioral Sciences,
George Washington University School of Medicine and Health Sciences,
Washington, DC

Lisa M. Jacola, PhD, ABPP-CN, Department of Psychology and Biobehavioral
Sciences, St. Jude Children's Research Hospital, Memphis, TN

Jordan Gilleland Marchak, PhD, ABPP, Emory University School of Medicine
and Aflac Cancer and Blood Disorders Center at Children's Healthcare of
Atlanta, Atlanta, GA

Iris Paltin, PhD, ABPP-CN, Division of Oncology, The Children's Hospital
of Philadelphia Department of Child and Adolescent Psychiatry and
Behavioral Sciences, University of Pennsylvania Perelman School of
Medicine, Philadelphia, PA

Wendy Pelletier MSW, RSW, Department of Oncology, Division of
Psychosocial Oncology, Cumming School of Medicine, University of
Calgary, Calgary, Alberta, Canada

Katie A. Devine, PhD, MPH, Department of Pediatrics, Rutgers Cancer
Institute of New Jersey, New Brunswick, NJ

Corresponding author:

Leanne Embry, PhD

Department of Pediatrics

University of Texas Health Science Center at San Antonio

San Antonio, Texas

Phone: 210-567-7481

Email: embryl@uthscsa.edu

Abstract word count: 216

Text word count: 3484

Tables/figures: 2

Funding support: Grant support from the National Institute of Health,
U10CA180886, U10CA180899, UG1CA189955.

\textbf{Abstract}

As survival rates for childhood cancer have improved, there has been
increasing focus on identifying and addressing adverse impacts of cancer
and its treatment on children and their families during treatment and
into survivorship. The Behavioral Science Committee (BSC) of the
Children's Oncology Group (COG), comprised of psychologists,
neuropsychologists, social workers, nurses, physicians, and clinical
research associates, aims to improve the lives of children with cancer
and their families through research and dissemination of empirically
supported knowledge. Key achievements of the BSC include enhanced
interprofessional collaboration through integration of liaisons into
other key committees within COG, successful measurement of critical
neurocognitive outcomes through standardized neurocognitive assessment
strategies, contributions to evidence-based guidelines, and optimization
of patient-reported outcome measurement. The collection of
neurocognitive and behavioral data continues to be an essential function
of the BSC, in the context of therapeutic trials that are modifying
treatments to maximize event-free survival, minimize adverse outcomes,
and optimize quality of life. In addition, through hypothesis-driven
research and multi-disciplinary collaborations, the BSC will also begin
to prioritize initiatives to expand the systematic collection of
predictive factors (e.g., social determinants of health) and
psychosocial outcomes, with overarching goals of addressing health
inequities in cancer care and outcomes, and promoting evidence-based
interventions to improve outcomes for all children, adolescents, and
young adults with cancer.

\textbf{Key Words} : behavioral science, pediatric cancer, psychosocial,
quality of life, supportive care, late effects

\textbf{Background}

Therapeutic advancements over the past 50 years have resulted in
survival rates of over 80\% for children diagnosed with cancer in the
US.\textsuperscript{1} Unfortunately, life-saving therapy is associated
with adverse late effects that may impact survivors long after treatment
ends.\textsuperscript{2} For many children, treatment includes intensive
regimens that disrupt typical psychosocial development and challenge the
family system in unique ways. Distress among family caregivers often
peaks at diagnosis and has garnered greater attention in the research
literature over the past decade.\textsuperscript{3} With improved
survival outcomes, efforts to optimize quality of life (QOL), including
neurocognitive, behavioral, and psychosocial outcomes, take on increased
importance.

Although most children adapt well to diagnosis and treatment, vulnerable
sub-groups remain. Children at highest risk for short- and long-term
neurobehavioral problems are those with central nervous system (CNS)
tumors, disease that requires CNS-targeted therapy, and children with
pre-existing individual or familial risk
factors.\textsuperscript{4}Multiple social and psychological factors
(e.g., race/ethnicity, socioeconomic status, family dynamics, trauma
history, etc.) contribute to psychosocial outcomes and the trajectory of
adaptation from diagnosis to survivorship.\textsuperscript{5} Members of
the Children's Oncology Group (COG) Behavioral Science Committee (BSC)
are researchers and clinicians dedicated to examining the psychosocial
impact of pediatric cancer and its treatment, during and after therapy,
on children and their families.

\emph{Behavioral Science Committee}

The mission of the BSC is to improve the lives and outcomes of children
with cancer and their families through research and dissemination of
empirically supported knowledge. The BSC recognizes that children with
cancer and their families have unique needs requiring targeted
scientific investigation and clinical implementation. The committee also
seeks to educate professional and lay communities to promote better
understanding and care of children with cancer and their families.

Comprised largely of psychologists and neuropsychologists, the BSC
enjoys a diverse membership that includes social workers, nurses,
physicians, and clinical research associates. These interdisciplinary
collaborations, and the extensive training that psychologists and
neuropsychologists receive in research design and outcome measurement,
allow the BSC to lead and contribute meaningfully to the planning and
conduct of QOL, behavioral and neurocognitive studies, and the
development, implementation and dissemination of behavioral science
interventions. Importantly, BSC members contribute perspectives of
behavioral health researchers and clinicians who work with children with
cancer, and their families, to discussions of COG practices including
informed consent, return of research results, empirically supported
interventions, and management of late effects. BSC members collaborate
in empirical research within COG on behavioral science interventions
that are both child- (pharmacological and/or behavioral) and
systems-directed (family, school, health care providers).

COG offers advantages for conducting collaborative research in pediatric
oncology. Examining behavioral science outcomes in the setting of
clinical trials is essential to help determine the differential impact
of new chemotherapy agents, varied treatment regimens, and therapy
reduction on behavioral health outcomes. Because most pediatric cancers
are rare, cooperative group research allows for large, diverse, and
representative sample sizes to be statistically powered to answer
research questions using homogeneous samples. It also provides the
opportunity to examine risk and protective factors beyond what is
possible in single institution studies.

\textbf{Key Achievements}

\emph{Liaison program}

BSC representatives are appointed as liaisons and integrated into key
steering committees of other Disease, Discipline, Domain, and
Administrative Committees within COG (Table 1). This structure
facilitates collaboration across committees and provides opportunities
for BSC involvement in the earliest stages of new concept development.
The BSC emphasizes mentoring future generations of investigators via
participation in the Young Investigators (YI) Committee mentorship
program. The BSC appoints two representatives (YI paired with an
experienced researcher) to every new study committee with behavioral
science outcomes (e.g., neurocognitive, QOL, or patient-reported
outcomes). BSC members included on study committees help refine research
questions, provide rationale for inclusion of cognitive/QOL endpoints,
and design assessment approaches. Table 2 summarizes BSC-relevant aims
in active trials.

\emph{Neurocognitive Assessment Strategies}

Historically, the BSC was primarily tasked with assessment and data
collection in trials examining neurocognitive outcomes in response to
treatment modifications. Our first concerted effort was the development
of a free-standing protocol, ALTE07C1, designed to streamline and
standardize neurocognitive data collection across COG trials. ALTE07C1
included a brief, direct assessment of cognitive domains commonly
affected by cancer and its treatment and predictive of
educational/occupational outcomes. A total of 945 children were enrolled
on this protocol across COG trials over a span of 14 years, representing
significantly improved data collection rates compared to prior COG
trials. ALTE07C1 has been renamed the COG Standardized Neurocognitive
Assessment Battery and is now embedded in relevant clinical trials.

After the development of ALTE07C1, BSC members began investigating the
utility of a briefer, computerized assessment battery
(Cogstate)\textsuperscript{6} that can be administered without a
psychologist or neuropsychologist. These computerized assessments have
the potential to characterize neurocognitive functioning with less cost,
time, practice effects, and patient burden than traditional measures.
However, there are minimal data linking these measures to functional
(educational/occupational) outcomes. With this in mind, BSC members
obtained R01 grant funding to develop a comprehensive model of
neurocognitive development in children with high-risk acute
lymphoblastic leukemia to guide prediction of individual risk for
cognitive declines and inform intervention development and timing.
Relying on an early detection model of frequent neurocognitive
monitoring, this initiative uses a multi-method approach of Cogstate
(embedded in protocol AALL1131) and traditional measures (ALTE07C1) to
understand neurocognitive function during and after treatment. Data
collection is ongoing, and analysis is pending.

\emph{Evidence-based Guidelines}

The BSC contributes to the development and endorsement of clinical
practice guidelines to support behavioral health (e.g., mental,
neurocognitive, psychosocial) across the cancer continuum from active
treatment to long-term survivorship. To guide patient care during
therapy, the COG Supportive Care Guidelines are a resource for
up-to-date guidelines aligned with Institute of Medicine
criteria\textsuperscript{7} that are reviewed, evaluated, and endorsed
by the COG Supportive Care Guidelines sub-Committee
(https://www.childrensoncologygroup.org/cog-supportive-care-endorsed-guidelines).
Currently, there are COG-endorsed guidelines to assist in the
psychosocial management of fatigue\textsuperscript{8} and chronic
pain.\textsuperscript{9} However, there remains a critical gap in
supportive care clinical practice guidelines that meet current
methodological standards.\textsuperscript{10}

BSC members help to evaluate recent evidence on potential behavioral
health late effects of treatment and generate recommended surveillance
in the COG Long-Term Follow-Up Guidelines
(http://www.survivorshipguidelines.org). These guidelines recommend
annual assessment for educational and vocational progress, social
functioning, mental health disorders, risky health behaviors, sleep,
fatigue, and healthcare or insurance access for all long-term survivors.
For patients with a history of exposure to neurotoxic therapy,
guidelines recommend formal neuropsychological evaluation upon entry to
survivorship care with repeated evaluations as needed for survivors with
impairments in educational or vocational progress. Despite the wealth of
observational data documenting neurocognitive and behavioral health late
effects and associated risk factors, interventions to address these late
effects of treatment are lacking and desperately needed to promote QOL
among long-term survivors.\textsuperscript{11--16}

\emph{Adolescents and Young Adults (AYAs)}

AYAs, defined by the National Cancer Institute (NCI) as ages 15-39
years, are a vulnerable group in cancer care due to biologic and genetic
differences, as well as risk factors that uniquely impact health and QOL
outcomes, including concerns related to clinical trial access and
enrollment, reproductive and sexual health, socioeconomic hardship, and
mental health/psychosocial functioning.\textsuperscript{17} Through BSC
liaison work with COG's AYA Committee, cross-network collaboration with
AYA investigators in medical oncology, and involvement in specific task
forces, the BSC is poised to help address gaps in supportive care AYA
research.

Given BSC expertise in QOL and patient-reported outcome (PRO)
measurement, the BSC liaison was invited to join the National Clinical
Trials Network (NCTN) AYA PRO Task Force formed in 2020. This task force
yielded an AYA PRO core battery to assess health-related QOL and
study-specific symptom burden, with recommended time points from study
entry into survivorship.\textsuperscript{18} Inclusion and evaluation of
the implementation of this battery in AYA clinical trials is underway.

BSC members also have significant expertise in psychosocial development;
thus, members are represented on the Sexual Health Task Force (SHTF) of
COG'S AYA Committee. This task force aims to identify knowledge gaps and
prioritize research questions to improve the quality of sexual health
care for AYAs. The SHTF conducted a scoping review of sexual health
among AYA cancer survivors that highlighted the post-treatment burden of
sexual dysfunction and negative impact of cancer on romantic
relationships and body image.\textsuperscript{19} The SHTF also
conducted a COG-wide survey of pediatric oncologists and advanced
practice providers that suggested a need for provider education on AYA
sexual health assessment, management, and
communication.\textsuperscript{20} Following the approach of the AYA PRO
Task Force, the SHTF created a sexual health PRO battery with potential
sexual health study endpoints for future inclusion in COG and
cross-network trials. Future initiatives will focus on provider
education and AYA patient-focused interventions to improve
provider-patient sexual health communication and care.

\textbf{Select Studies with BSC Involvement}

\emph{Acute lymphoblastic leukemia (ALL)}

ALL is the most common childhood malignancy; survival rates exceed
90\%.\textsuperscript{21,22} Treatment modifications have substantially
reduced neurocognitive late effects, but survivors continue to
demonstrate neurocognitive impairments secondary to disease and
treatment that impacts educational/occupational
outcomes.\textsuperscript{23}

COG AALL1731 for children with newly diagnosed NCI standard-risk B-ALL,
including children with Down syndrome and ALL (DS-ALL) examines whether
treatment with blinatumomab in combination with chemotherapy lowers the
risk for relapse and increases survival. AALL1731 includes embedded
neurocognitive studies that will lay the groundwork for future
risk-based neurocognitive screening and targeted interventions to
improve survivors' QOL.

Recognizing the importance of the relationship between neurocognition
and poverty,\textsuperscript{24} AALL1731 includes the first
comprehensive investigation of poverty-related neurocognitive outcome
disparities in pediatric standard risk B-ALL. This embedded study
explores whether children living in poverty (defined as presence of
household material hardship -- food, housing, or energy insecurity) at
the time of diagnosis, are at risk for greater neurocognitive declines
from baseline measured via Cogstate than their less impoverished
counterparts. Additionally, among a subset of children enrolled in the
household material hardship neurocognitive study, there is an aim
investigating the impact of blinatumomab on caregiver burden and PROs.
Finally, AALL1731 includes the first prospective study of neurocognitive
outcomes in children with DS-ALL. Despite increased vulnerability to
leukemia\textsuperscript{25,26} and treatment
toxicities,\textsuperscript{27,28} these patients have been
systematically excluded from decades of neurocognitive studies in
childhood ALL\textsuperscript{23} and thus very little is known about
their neurocognitive outcomes. The DS-ALL neurocognitive study
investigates individual, clinical, and socioenvironmental determinants
of neurocognitive and QOL outcomes. Findings will drive the future
inclusion of individuals with DS-ALL in evidence-based clinical practice
guidelines for neurocognitive screening, survivorship care, and
interventions.

\emph{Acute Promyelocytic Leukemia (APL)}

APL is highly curable with existing therapies; therefore, there has been
movement towards developing protocols that are less reliant on
potentially cardiotoxic anthracycline chemotherapy. AAML1331 evaluated
whether treating pediatric patients with APL using arsenic trioxide and
all-trans retinoic acid would allow for a reduced or eliminated need for
chemotherapy while maintaining high rates of event-free
survival.\textsuperscript{29} Environmental arsenic exposures confer
serious risks to the developing brain\textsuperscript{30,31} and, while
arsenic trioxide is not thought to cross the blood-brain barrier, there
have been reports of arsenic concentrations in the cerebrospinal fluid
of patients treated with arsenic trioxide.\textsuperscript{32,33}

Neurocognitive aims were included in protocol AAML1331. This study
represented an important shift in approach that sought to demonstrate
the feasibility of incorporating the neurocognitive assessment battery
developed on ALTE07C1 into a therapeutic clinical trial rather than
enrolling patients separately on the standalone ALTE07C1 protocol. The
optional neurocognitive study was well-received by the AAML1331 study
committee and participating COG sites, as patients were enrolled at 73
different institutions (86\% of all AAML1331 sites). There was also
strong interest from families, as the accrual target was reached early,
and the study was granted special permission to over-enroll. Data
collection is ongoing and, when complete, will clarify the short- and
long-term safety of arsenic trioxide for the treatment of pediatric APL.

\emph{CNS Tumors}

Children treated for brain tumors are at greatest cognitive risk given
tumor mass effect and CNS-directed
therapy.\textsuperscript{34}Accordingly, many of the current trials
emerging from the COG CNS committee center around modifying front-line
therapy to maintain high survival rates (e.g., non-inferiority trials)
while improving QOL. Since ALTE07C1 was discontinued as a free-standing
protocol, there have been more than 10 new studies developed within the
CNS committee that include cognitive and/or QOL assessments,
highlighting the importance of collaborations with the BSC.

BSC members are also actively involved in intervention trials that seek
to mitigate the emergence of cognitive late effects. ACCL2031 is a prime
example whereby memantine, a glutamatergic NMDA receptor antagonist, is
being investigated as a neuroprotectant in a randomized,
placebo-controlled trial. Memantine has been shown to be neuroprotective
in preclinical models\textsuperscript{35,36} and resulted in less
cognitive decline among adults receiving whole brain radiation therapy
for brain metastases.\textsuperscript{37} ACCL2031 randomizes children
with primary CNS tumors, initiating cranial radiation therapy, to
memantine or placebo. Change in cognitive functioning is the primary
outcome for this trial. Cogstate and parent-reported executive function
are required assessments for monitoring outcomes; the COG Standardized
Neurocognitive Assessment Battery is recommended but not required. Trial
enrollment is underway for this NCI-funded study. Notably, positive
study findings would suggest cognitive late effects can be
prophylactically ameliorated or even prevented.

\textbf{Persistent Challenges}

Like other Discipline Committees in the cooperative group, the BSC
cannot develop and lead free-standing trials. Partnership with disease
and domain committees is therefore critical to promote behavioral
science aims early in concept development. There are logistical
challenges to conducting behavioral science research in a cooperative
group setting. As a more specialized discipline, some COG institutions
do not have a BSC member to champion relevant studies at their site. In
fact, some sites do not have ready access to psychology or
neuropsychology, even for clinical services. Traditional assessments of
neurocognitive function require a licensed
psychologist/neuropsychologist for administration, prohibiting
feasibility of this type of research in under-resourced institutions. In
addition, some of the most psychometrically robust measures of
neurocognition and QOL are copyrighted and have an associated cost,
which can be burdensome at the institutional level; funding is not
always available at the NCI level to help offset costs of materials or
management of these data. There are often not resources to administer
these measures in languages other than English, Spanish, or French,
limiting our ability to meet the need of some vulnerable or marginalized
populations.

Furthermore, behavioral science endpoints are often secondary or
exploratory aims embedded in therapeutic trials, resulting in long waits
for analysis, particularly when evaluating long-term follow-up. For
example, if a study aims to examine cognitive functioning at 5 years
post-diagnosis, and the study accrues patients over a 5-year period,
complete data for the behavioral science aim would not be available
until 10 years after trial initiation. This can be a prohibitive
timeline for investigators, especially YIs, who put significant effort
into the planning and activation of a trial but must wait a long time
for tangible products such as publications. This demonstrates the long
time between research evidence and translation to routine care.

\textbf{Strategic Plan: Opportunities and Future Directions}

With significant improvements in cancer treatment, clinical trials have
moved towards a precision medicine framework with scientific aims
focused on optimizing QOL and minimizing toxicities while maintaining
high survival rates. COG offers a unique collaborative environment to
evaluate scientific aims with behavioral science outcomes in the context
of large clinical trials with representative samples of children and
AYAs with cancer from diverse racial, ethnic, and socioeconomic
backgrounds. Aligned with our mission to improve outcomes for children
with cancer and their families, the BSC is poised to contribute to the
scientific advances of trials aiming to improve outcomes and promote
evidence-based supportive care interventions to be translated into
routine care.

\emph{Optimizing Patient-Reported Outcomes Data}

Following the success of the AYA PRO Task Force\textsuperscript{18},
leaders from the BSC, Nursing, and Cancer Control committees are
co-leading a new PRO Optimization Task Force to enhance the capacity and
efficiency of patient- and caregiver-reported outcomes among youth
\textless{}15 years of age. Valid measurement of PROs is essential to
ongoing and future clinical trials focused on improving patient and
family functioning during and after cancer treatment. There are many
unique issues to consider for this age group, including the inclusion of
multiple raters (e.g., child, caregiver, teacher) to account for
developmental differences and functioning across settings and the wide
range of cognitive, social, and emotional outcomes. This task force aims
to develop a PRO battery to address the unique needs of children that is
flexible to address study-specific aims. Other goals include expanding
expertise within COG for the design and analysis of PRO endpoints, and
developing infrastructure for optimal and efficient (i.e., electronic)
capture of PRO data.

\emph{Prioritizing Social Determinants of Health (SDOH)}

The BSC strongly supports ongoing work to identify and address health
disparities in pediatric and AYA cancer care. In particular, the impact
of household material hardship and adverse SDOH on pediatric oncology
patients is well established in the literature.\textsuperscript{38--40}

Although the gains achieved in cure rates in pediatric oncology may be
attributed in large part to clinical trial organizations, children
living in poverty and those identified as being from marginalized
racial, ethnic, and minority groups are more likely to relapse and die
at rates different from their non-Hispanic White
counterparts.\textsuperscript{41--44} Biology, tumor genetics, and
response to initial therapy aside, pre-existing social and psychological
factors, including SDOH, play a significant role in patient
outcomes.\textsuperscript{45,46}

Financial toxicity has been categorized as direct expenditures
associated with treatment and access, and the indirect costs families
sustain throughout the treatment trajectory related to loss of income
and educational opportunities. Further, financial toxicity is
detrimental to parental mental health and family
functioning.\textsuperscript{47--49}

Despite awareness of the multifaceted disparities and inequities in
pediatric cancer, the systematic collection of information on SDOH and
socioeconomic status has not been included in clinical
trials.\textsuperscript{50}Collaborative, multidisciplinary research
studies within COG are beginning to embed these measures within clinical
trials to better understand these factors and design interventions to
ensure equitable access to, and benefit from,
treatment.\textsuperscript{51,52}

\emph{Recognizing Underserved Populations}

The BSC has established two working groups within the committee to focus
on underserved groups: AYA and Infants/Young Children. The AYA working
group consists of nine BSC members with expertise in cognitive and
psychosocial functioning in AYA Oncology. The primary objective is to
generate behavioral science-focused study concepts that are salient and
impactful for the AYA cancer population that can be successfully
implemented as large-scale, free-standing COG and cross-network trials.
The Infants/Young Children working group consists of seven BSC members
with expertise in the cognitive, social-emotional, and physical
development of very young children. The primary objective is to generate
recommendations for valid measurement of important outcomes for this
group that can be feasibly implemented in the cooperative group setting,
and to promote healthy development and preventative interventions for
very young children and their caregivers.

\emph{Expanding BSC Involvement}

The collection of neurocognitive and behavioral data in the context of
clinical trials that are modifying treatment to minimize neurotoxicity
continues to be paramount. The BSC will continue to work toward
balancing the efficiency of computerized assessments with the more
clinically relevant but time-intensive traditional,
psychologist-administered measures of cognitive functioning. We will
begin to address the exclusion of some marginalized populations from
participation in cognitive outcomes research related to the lack of
availability of testing materials in languages other than English,
Spanish, and French. Relevant to cognitive outcomes, efforts are
underway to examine the impact of anesthesia exposure over time,
particularly in survivors of ALL. We will also be examining the impact
of sensory deficits (i.e., vision/ hearing impairment) resulting from
cancer or its treatment on cognitive outcomes and QOL.

There is a substantial breadth of expertise in the BSC that extends
beyond neurocognitive functioning. Feasible interventions to address
psychosocial and mental health late effects of treatment are lacking and
desperately needed to promote QOL among long-term survivors of childhood
cancer.\textsuperscript{11--16} There is particular interest in
dissemination and implementation science, including promoting the use of
and adherence to evidence-based interventions. Studies are needed to
examine how children with cancer perform at school -- both academically
and socially/emotionally -- and what kinds of supports are required
after treatment (e.g., 504/IEP, special education). Future research must
focus on gathering data related to social attainment and its barriers,
particularly among AYAs, including rates of graduation, employment, and
independent living. Finally, there is interest in standardizing methods
of distress screening and developing brief, feasible methods of reducing
distress among patients of all ages and their families.

\textbf{Conclusion}

In the coming years, the BSC will prioritize initiatives focused on
expanding the systematic collection of cognitive and psychosocial
outcomes and predictive factors across trials, identifying and
addressing health inequities in cancer care and outcomes, and promoting
evidence-based interventions to improve outcomes for all children, AYAs,
and their caregiver. The inclusion of behavioral science aims permits
simultaneous evaluation of the neurocognitive and psychosocial impact
associated with new advances in treatment. It also helps to expand the
pool of COG investigators with expertise in behavioral science and PROs.
Through collaborative efforts across COG, the BSC is well-positioned to
improve the measurement of relevant outcomes, develop salient
interventions, and begin addressing health disparities.

\textbf{References}

1. Siegel DA, Richardson LC, Henley SJ, et al. Pediatric cancer
mortality and survival in the United States, 2001-2016. \emph{Cancer} .
2020;126(19):4379-4389. doi:10.1002/cncr.33080

2. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children.
Longo DL, ed. \emph{N Engl J Med} . 2015;373(16):1541-1552.
doi:10.1056/NEJMra1400972

3. Cusinato M, Calvo V, Bisogno G, et al. Attachment orientations and
psychological adjustment of parents of children with cancer: A
matched-group comparison. \emph{Journal of Psychosocial Oncology} .
2017;35(6):726-740. doi:10.1080/07347332.2017.1335365

4. Brinkman TM, Recklitis CJ, Michel G, Grootenhuis MA, Klosky JL.
Psychological Symptoms, Social Outcomes, Socioeconomic Attainment, and
Health Behaviors Among Survivors of Childhood Cancer: Current State of
the Literature. \emph{J Clin Oncol} . 2018;36(21):2190-2197.
doi:10.1200/JCO.2017.76.5552

5. Kazak AE, Noll RB. The integration of psychology in pediatric
oncology research and practice: Collaboration to improve care and
outcomes for children and families. \emph{American Psychologist} .
2015;70(2):146-158. doi:10.1037/a0035695

6. Maruff P, Thomas E, Cysique L, et al. Validity of the CogState Brief
Battery: Relationship to Standardized Tests and Sensitivity to Cognitive
Impairment in Mild Traumatic Brain Injury, Schizophrenia, and AIDS
Dementia Complex. \emph{Archives of Clinical Neuropsychology} .
2009;24(2):165-178. doi:10.1093/arclin/acp010

7. Institute of Medicine (US) Committee on Standards for Developing
Trustworthy Clinical Practice Guidelines. \emph{Clinical Practice
Guidelines We Can Trust} . (Graham R, Mancher M, Miller Wolman D,
Greenfield S, Steinberg E, eds.). National Academies Press (US); 2011.
Accessed May 24, 2023. http://www.ncbi.nlm.nih.gov/books/NBK209539/

8. Robinson PD, Oberoi S, Tomlinson D, et al. Management of fatigue in
children and adolescents with cancer and in paediatric recipients of
haemopoietic stem-cell transplants: a clinical practice
guideline.\emph{Lancet Child Adolesc Health} . 2018;2(5):371-378.
doi:10.1016/S2352-4642(18)30059-2

9. \emph{Guidelines on the Management of Chronic Pain in Children} .
World Health Organization; 2020. Accessed May 24, 2023.
http://www.ncbi.nlm.nih.gov/books/NBK566553/

10. Seelisch J, Sung L, Kelly MJ, et al. Identifying clinical practice
guidelines for the supportive care of children with cancer: A report
from the Children's Oncology Group. \emph{Pediatr Blood Cancer} .
2019;66(1):e27471. doi:10.1002/pbc.27471

11. Schulte F, Kunin-Batson AS, Olson-Bullis BA, et al. Social
attainment in survivors of pediatric central nervous system tumors: a
systematic review and meta-analysis from the Children's Oncology
Group.\emph{J Cancer Surviv} . 2019;13(6):921-931.
doi:10.1007/s11764-019-00808-3

12. Devine KA, Christen S, Mulder RL, et al. Recommendations for the
surveillance of education and employment outcomes in survivors of
childhood, adolescent, and young adult cancer: A report from the
International Late Effects of Childhood Cancer Guideline Harmonization
Group. \emph{Cancer} . 2022;128(13):2405-2419. doi:10.1002/cncr.34215

13. Gilleland Marchak J, Devine KA, Hudson MM, et al. Systematic Review
of Educational Supports of Pediatric Cancer Survivors: Current
Approaches and Future Directions. \emph{J Clin Oncol} .
2021;39(16):1813-1823. doi:10.1200/JCO.20.02471

14. Marchak JG, Christen S, Mulder RL, et al. Recommendations for the
surveillance of mental health problems in childhood, adolescent, and
young adult cancer survivors: a report from the International Late
Effects of Childhood Cancer Guideline Harmonization Group. \emph{Lancet
Oncol} . 2022;23(4):e184-e196. doi:10.1016/S1470-2045(21)00750-6

15. Christen S, Roser K, Mulder RL, et al. Recommendations for the
surveillance of cancer-related fatigue in childhood, adolescent, and
young adult cancer survivors: a report from the International Late
Effects of Childhood Cancer Guideline Harmonization Group. \emph{J
Cancer Surviv} . 2020;14(6):923-938. doi:10.1007/s11764-020-00904-9

16. Schulte FSM, Patton M, Alberts NM, et al. Pain in long-term
survivors of childhood cancer: A systematic review of the current state
of knowledge and a call to action from the Children's Oncology
Group.\emph{Cancer} . 2021;127(1):35-44. doi:10.1002/cncr.33289

17. Close AG, Dreyzin A, Miller KD, Seynnaeve BKN, Rapkin LB. Adolescent
and young adult oncology-past, present, and future. \emph{CA Cancer J
Clin} . 2019;69(6):485-496. doi:10.3322/caac.21585

18. Roth ME, Parsons SK, Ganz PA, et al. Inclusion of a core
patient-reported outcomes battery in adolescent and young adult cancer
clinical trials. \emph{J Natl Cancer Inst} . 2023;115(1):21-28.
doi:10.1093/jnci/djac166

19. Cherven B, Sampson A, Bober SL, et al. Sexual health among
adolescent and young adult cancer survivors: A scoping review from the
Children's Oncology Group Adolescent and Young Adult Oncology Discipline
Committee. \emph{CA Cancer J Clin} . 2021;71(3):250-263.
doi:10.3322/caac.21655

20. Frederick NN, Bingen K, Bober SL, et al. Pediatric oncology
clinician communication about sexual health with adolescents and young
adults: A report from the children's oncology group. \emph{Cancer Med} .
2021;10(15):5110-5119. doi:10.1002/cam4.4077

21. Noone A, Howlander N, Krapcho M, et al. SEER Cancer Statistics
Review, 1975-2015. SEER. Published 2018. Accessed May 24, 2023.
https://seer.cancer.gov/archive/csr/1975\_2015/index.html

22. Pui CH, Evans WE. A 50-year journey to cure childhood acute
lymphoblastic leukemia. \emph{Semin Hematol} . 2013;50(3):185-196.
doi:10.1053/j.seminhematol.2013.06.007

23. van der Plas E, Modi AJ, Li CK, Krull KR, Cheung YT. Cognitive
Impairment in Survivors of Pediatric Acute Lymphoblastic Leukemia
Treated With Chemotherapy Only. \emph{J Clin Oncol} .
2021;39(16):1705-1717. doi:10.1200/JCO.20.02322

24. Johnson SB, Riis JL, Noble KG. State of the Art Review: Poverty and
the Developing Brain. \emph{Pediatrics} . 2016;137(4):e20153075.
doi:10.1542/peds.2015-3075

25. Hasle H. Pattern of malignant disorders in individuals with Down's
syndrome. \emph{Lancet Oncol} . 2001;2(7):429-436.
doi:10.1016/S1470-2045(00)00435-6

26. Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid
tumours in individuals with Down's syndrome. \emph{Lancet} .
2000;355(9199):165-169. doi:10.1016/S0140-6736(99)05264-2

27. Athale UH, Puligandla M, Stevenson KE, et al. Outcome of children
and adolescents with Down syndrome treated on Dana-Farber Cancer
Institute Acute Lymphoblastic Leukemia Consortium protocols 00-001 and
05-001. \emph{Pediatr Blood Cancer} . 2018;65(10):e27256.
doi:10.1002/pbc.27256

28. Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic
leukemia in children with Down syndrome: a retrospective analysis from
the Ponte di Legno study group. \emph{Blood} . 2014;123(1):70-77.
doi:10.1182/blood-2013-06-509463

29. Kutny MA, Alonzo TA, Abla O, et al. Assessment of Arsenic Trioxide
and All-trans Retinoic Acid for the Treatment of Pediatric Acute
Promyelocytic Leukemia: A Report From the Children's Oncology Group
AAML1331 Trial. \emph{JAMA Oncol} . 2022;8(1):79.
doi:10.1001/jamaoncol.2021.5206

30. Tolins M, Ruchirawat M, Landrigan P. The Developmental Neurotoxicity
of Arsenic: Cognitive and Behavioral Consequences of Early Life
Exposure. \emph{Annals of Global Health} . 2014;80(4):303-314.
doi:10.1016/j.aogh.2014.09.005

31. Vaidya N, Holla B, Heron J, et al. Neurocognitive Analysis of
Low-level Arsenic Exposure and Executive Function Mediated by Brain
Anomalies Among Children, Adolescents, and Young Adults in
India.\emph{JAMA Netw Open} . 2023;6(5):e2312810.
doi:10.1001/jamanetworkopen.2023.12810

32. Knipp S, Gattermann N, Schapira M, K\selectlanguage{ngerman}äferstein H, Germing U. Arsenic
in the cerebrospinal fluid of a patient receiving arsenic trioxide for
relapsed acute promyelocytic leukemia with CNS
involvement.\emph{Leukemia Research} . 2007;31(11):1585-1587.
doi:10.1016/j.leukres.2007.03.007

33. Au WY, Tam S, Fong BM, Kwong YL. Determinants of cerebrospinal fluid
arsenic concentration in patients with acute promyelocytic leukemia on
oral arsenic trioxide therapy. \emph{Blood} . 2008;112(9):3587-3590.
doi:10.1182/blood-2008-06-161000

34. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late
neurocognitive sequelae in survivors of brain tumours in
childhood.\emph{Lancet Oncol} . 2004;5(7):399-408.
doi:10.1016/S1470-2045(04)01507-4

35. Pellegrini JW, Lipton SA. Delayed administration of memantine
prevents N-methyl-D-aspartate receptor-mediated neurotoxicity. \emph{Ann
Neurol} . 1993;33(4):403-407. doi:10.1002/ana.410330414

36. Liu C, Lin N, Wu B, Qiu Y. Neuroprotective effect of memantine
combined with topiramate in hypoxic-ischemic brain injury. \emph{Brain
Res} . 2009;1282:173-182. doi:10.1016/j.brainres.2009.05.071

37. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of
cognitive dysfunction in patients receiving whole-brain radiotherapy: a
randomized, double-blind, placebo-controlled trial. \emph{Neuro Oncol} .
2013;15(10):1429-1437. doi:10.1093/neuonc/not114

38. Santacroce SJ, Kneipp SM. A Conceptual Model of Financial Toxicity
in Pediatric Oncology. \emph{J Pediatr Oncol Nurs} . 2019;36(1):6-16.
doi:10.1177/1043454218810137

39. Tran YH, Coven SL, Park S, Mendonca EA. Social determinants of
health and pediatric cancer survival: A systematic review. \emph{Pediatr
Blood Cancer} . 2022;69(5):e29546. doi:10.1002/pbc.29546

40. Pelletier W, Bona K. Assessment of Financial Burden as a Standard of
Care in Pediatric Oncology. \emph{Pediatr Blood Cancer} . 2015;62 Suppl
5:S619-631. doi:10.1002/pbc.25714

41. Aristizabal P, Winestone LE, Umaretiya P, Bona K. Disparities in
Pediatric Oncology: The 21st Century Opportunity to Improve Outcomes for
Children and Adolescents With Cancer. \emph{Am Soc Clin Oncol Educ Book}
. 2021;41:e315-e326. doi:10.1200/EDBK\_320499

42. Scheurer ME, Lupo PJ, Schüz J, et al. An overview of disparities in
childhood cancer: Report on the Inaugural Symposium on Childhood Cancer
Health Disparities, Houston, Texas, 2016. \emph{Pediatric Hematology and
Oncology} . 2018;35(2):95-110. doi:10.1080/08880018.2018.1464088

43. Gupta S, Wilejto M, Pole JD, Guttmann A, Sung L. Low socioeconomic
status is associated with worse survival in children with cancer: a
systematic review. \emph{PLoS One} . 2014;9(2):e89482.
doi:10.1371/journal.pone.0089482

44. Bhatia S. Disparities in cancer outcomes: lessons learned from
children with cancer. \emph{Pediatr Blood Cancer} . 2011;56(6):994-1002.
doi:10.1002/pbc.23078

45. Gupta S, Teachey DT, Devidas M, et al. Racial, Ethnic, and
Socioeconomic Factors Result in Disparities in Outcome Among Children
with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease
Prognosticators: A Children's Oncology Group (COG) Study. \emph{Blood} .
2021;138(Supplement 1):211-213. doi:10.1182/blood-2021-147386

46. Newman H, Lee S, Pölönen P, et al. The Influence of Genetic Ancestry
on Disease Biology in Pediatric T-Cell Acute Lymphoblastic
Leukemia.\emph{Blood} . 2022;140(Supplement 1):3458-3460.
doi:10.1182/blood-2022-159159

47. Kelada L, Wakefield CE, Vetsch J, et al. Financial toxicity of
childhood cancer and changes to parents' employment after treatment
completion. \emph{Pediatr Blood Cancer} . 2020;67(7):e28345.
doi:10.1002/pbc.28345

48. Umaretiya PJ, Koch VB, Stevenson KE, et al. Household material
hardship and parental distress in a multicenter clinical trial for
pediatric acute lymphoblastic leukemia. \emph{JCO} .
2021;39(15\_suppl):10025-10025. doi:10.1200/JCO.2021.39.15\_suppl.10025

49. Ilowite MF, Al-Sayegh H, Ma C, et al. The Relationship Between
Household Income and Patient-Reported Symptom Distress and Quality of
Life in Children With Advanced Cancer: A Report From the PediQUEST
Study. \emph{Cancer} . 2018;124(19):3934-3941. doi:10.1002/cncr.31668

50. Bona K, Keating NL. Addressing Social Determinants of Health: Now Is
the Time. \emph{JNCI: Journal of the National Cancer Institute} .
2022;114(12):1561-1563. doi:10.1093/jnci/djac137

51. Aziz-Bose R, Zheng DJ, Umaretiya PJ, et al. Feasibility of oncology
clinical trial-embedded evaluation of social determinants of
health.\emph{Pediatr Blood Cancer} . 2022;69(11):e29933.
doi:10.1002/pbc.29933

52. Beauchemin M, Santacroce SJ, Bona K, et al. Rationale and design of
Children's Oncology Group (COG) study ACCL20N1CD: financial distress
during treatment of acute lymphoblastic leukemia in the United
States.\emph{BMC Health Services Research} . 2022;22(1):832.
doi:10.1186/s12913-022-08201-0

\textbf{ACKNOWLEDGMENTS}

This work was supported by R01CA212190 and U01CA246568, as well as by
grants supporting activities of the Children's Oncology Group (NCTN
Operations Center Grant U10CA180886, NCTN Statistics \& Data Center
Grant U10CA180899, and NCORP UG1CA189955).

\textbf{TABLE OF ABBREVIATIONS}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ALL & Acute lymphoblastic leukemia\tabularnewline
\midrule
\endhead
APL & Acute promyelocytic leukemia\tabularnewline
AYA & Adolescent and young adult\tabularnewline
BSC & Behavioral Science Committee\tabularnewline
CNS & Central nervous system\tabularnewline
COG & Children's Oncology Group\tabularnewline
CV & Carboplatin/vincristine\tabularnewline
DS & Down syndrome\tabularnewline
HSCT & Hematopoietic stem cell transplant\tabularnewline
LGG & Low grade glioma\tabularnewline
NCI & National Cancer Institute\tabularnewline
NCTN & National Clinical Trials Network\tabularnewline
NF1 & Neurofibromatosis Type 1\tabularnewline
PRO & Patient-reported outcomes\tabularnewline
QOL & Quality of life\tabularnewline
SDOH & Social determinants of health\tabularnewline
SHTF & Sexual health task force\tabularnewline
YI & Young investigators\tabularnewline
\bottomrule
\end{longtable}

\textbf{Hosted file}

\verb`BSC Blueprint Table 1_final.docx`  available at \url{https://authorea.com/users/634235/articles/652192-children-s-oncology-group-s-2023-blueprint-for-research-behavioral-science}

\textbf{Hosted file}

\verb`BSC Blueprint Table 2_final.docx`  available at \url{https://authorea.com/users/634235/articles/652192-children-s-oncology-group-s-2023-blueprint-for-research-behavioral-science}

\selectlanguage{english}
\FloatBarrier
\end{document}

