Innovations in Cancer Treatment of

Children
Lauren Helms, MD,a,* Allison E. Guimera, MD,b,* Katherine A. Janeway, MD,c Kelly M. Bailey, MD, PhDd

Pediatric cancer outcomes have significantly improved, and yet this success is not abstract
spread equally across cancer types or patients. Disparities data in pediatric oncol-
ogy highlight needed improvements in access to care, including clinical trials and
advanced testing for all patients. For cancers such as brain tumors and sarcomas,
continued advancement in understanding the biology of tumor heterogeneity is
an essential step toward finding new therapeutic combinations to improve out-
comes. Pediatric cancer survivors need access to emerging technologies aimed at
reducing or better managing toxicities from therapy. With advances in treatment
and survival, pediatric oncology patients continue to need longitudinal, multidisci-
a
plinary subspecialty care. Refining the communication between pediatric oncolo- Department of Pediatrics, Michigan Medicine, Ann Arbor,
Michigan; bDepartment of Pediatrics, University of
gists, primary pediatricians, survivorship clinics, and adult primary care is key in California Los Angeles, Los Angeles, California;
c
ensuring the best lifelong care of pediatric cancer survivors. In this State-of-The- Dana-Farber/Boston Children’s Cancer and Blood
Disorders Center, Boston, Massachusetts; and dDivision of
Art review, we discuss 5 major domains in pediatric oncology: reducing toxicity, Pediatric Hematology and Oncology, Department of
cancer biology, novel therapies, detection and monitoring, and access to care, to Pediatrics, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania
highlight recent advances and areas for continued improvement.
Drs Helms and Guimera contributed to the manuscript
draft and figure editing; Drs Janeway and Bailey
conceptualized the article and contributed to the
In the past 50 years, pediatric cancer outcomes have greatly improved. Some can- manuscript draft; and all authors critically reviewed
and revised the manuscript, approved the final
cers, such as pediatric acute lymphoblastic leukemia, have demonstrated steady manuscript as submitted, and agree to be accountable
improvements in outcome throughout this time, with a 3-year survival in 1975 of for all aspects of the work.
59% and a 5-year survival in 2020 of 90%.1–4 Immunotherapy continues to *Contributed equally as co-first authors.
revolutionize the treatment of aggressive pediatric leukemias and lymphomas.5,6 DOI: https://doi.org/10.1542/peds.2023-061539
In contrast, after initial improvements in outcome because of the discovery and Accepted for publication Jul 24, 2023
use of chemotherapeutic agents such as doxorubicin and pediatric cancers such
Address correspondence to Kelly M. Bailey, MD, PhD, UPMC
as bone sarcomas, some brain tumors have not achieved meaningful survival im- Children’s Hospital of Pittsburgh, 5122 Rangos Research
provements with new therapies in decades.7 Broadly speaking, survival differ- Building, 4401 Penn Ave, Pittsburgh, PA 15224. E-mail:
kelly.bailey@chp.edu
ences have inspired 2 major research focuses in pediatric oncology: (1) for
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
patients with excellent (90%1) survival, we now seek ways to reduce or modify 1098-4275).
therapy to minimize long-term treatment complications, and (2) for patients diag- This is an open access article distributed under the terms of the
nosed with tumors stuck in a survival “plateau” (continued poor outcomes), we Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License (https://creativecommons.org/licenses/
turn to innovations in biology to determine new therapeutic vulnerabilities, en- by-nc-nd/4.0/), which permits noncommercial distribution and re-
hance disease monitoring, and better understand tumor heterogeneity, metastasis, production in any medium, provided the original author and
source are credited.
and treatment resistance.
Primary pediatricians are often the physicians first uncovering the atypical FUNDING: Dr Bailey is currently supported by the
National Institutes of Health (NCI K08CA252178) and
symptoms, abnormal physical exam findings, and concerning laboratory values would like to thank the UPMC Children’s Hospital
that ultimately lead to the workup and diagnosis of cancer in children. Sus- Foundation for their support. The other authors
received no additional funding.
pected malignant solid tumors in children most often require a biopsy to deter-
CONFLICT OF INTEREST DISCLOSURES: Dr Janeway has
mine a definitive diagnosis. Historically, the majority of these diagnostic served as a consultant for Bayer, Ipsen, and Illumina;
biopsies were open biopsies performed by pediatric or orthopedic surgeons. the other authors have indicated they have no potential
conflicts of interest to disclose.
Given innovations in image-guided percutaneous biopsy techniques, diagnostic
tumor core biopsies are performed by interventional radiologists and at many
institutions are now more common than open biopsies.8 Tumor molecular To cite: Helms L, Guimera AE, Janeway KA, et al.
Innovations in Cancer Treatment of Children.
profiling at the time of diagnosis is also now more prevalent and helps drive Pediatrics. 2023;152(6):e2023061539
personalized medicine efforts in pediatric oncology.9,10

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 PEDIATRIC CANCER TREATMENT TODAY: WHAT DOES IT LOOK event-free and overall survival).11 Despite these excellent
LIKE? outcomes, current treatment regimens result in signifi-
Although some children with specific subtypes of cancer cant risk of both short-term (during therapy) and long-
have benefitted from targeted therapies or immunothera- term (after therapy completion) side effects, and many
pies, the vast majority of children diagnosed with cancer pediatric cancer survivors are diagnosed with 1 or more
today are still treated with standard chemotherapy and chronic health issues.12–14 In the setting of overall excel-
sometimes surgery and/or radiation therapy. As more chil- lent outcomes, a logical next-step is to determine how to
dren survive pediatric cancer, primary care pediatricians better mitigate or treat toxicities while maintaining ex-
and pediatricians across subspecialties increasingly inter- cellent overall survival. Table 1 highlights examples of
act with childhood cancer survivors, children living with only some of the toxicities encountered during cancer di-
cancer, and their families (Fig 1). Pediatric cancer affects rected therapy to highlight the range of approaches to re-
almost every facet of child and adolescent health. This duce or avoid those long-term effects. These approaches
State-of-the-Art article aims to provide pediatricians with include future lifestyle modifications, protective medica-
an update on the state of pediatric cancer care. We high- tions, utilizing different chemotherapy regimens, and
broadly reducing exposure to agents by optimizing risk
light the following domains: reducing toxicity, cancer biol-
stratification (what patients can still have excellent out-
ogy, novel therapies, detection and monitoring, and access
comes with less chemotherapy or radiation exposure).
to care, because these domains both represent areas of
need for children with cancer and core topics in general Therapy Reduction
pediatric medicine, such as long-term health, medical re-
One approach to toxicity reduction is decreasing cumula-
search and advancement, and health disparities.
tive doses of chemotherapy. Again, using leukemia as an
example, chemotherapy is assigned by risk group. Pa-
REDUCING TOXICITY tients with standard risk leukemia are exposed to less
Thanks to cooperative national clinical trial efforts over cumulative anthracyclines as compared with patients
decades, some pediatric patients diagnosed with cancer, with high-risk leukemia.15,16 Further, historically boys re-
such as newly diagnosed standard risk B-cell lympho- ceived an additional year of maintenance chemotherapy
blastic leukemia, now have excellent outcomes (>90% for the treatment of B-cell lymphoblastic leukemia on

Reducing
Toxicity

Detection and Novel

Monitoring Therapies

Access to
Biology
Care

FIGURE 1
Overview of 5 major areas of advancement in pediatric oncology. Figures created with BioRender.com.

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 TABLE 1 Examples of Long-term Side Effects From Pediatric Cancer Treatment and Interventions
Examples of Long-term Side Effects From Examples of Interventions to Reduce
Cancer Type Therapy63–66 Long-term Side Effects63–66
Hodgkin lymphoma  Gonadal dysfunction: potential for reduced  Discussing options for fertility preservation
fertility or infertility in both males and females at diagnosis and during long-term follow-up
 Thyroid complication: hypothyroidism; visits
increased risk of thyroid cancer  Thyroid complications: decreased risk by
reducing utilization of radiation therapy
Acute lymphoblastic leukemia  Growth impairment including short stature,  Growth impairment: improved by the
precocious puberty, or delayed puberty replacement of cranial radiotherapy with
 Metabolic syndrome, obesity intrathecal chemotherapy
 Dietary and exercise interventions
Neuroblastoma  Hearing loss: related to exposure to platinum  Reduce the duration and intensity of
compounds treatment when possible through risk
 Cataracts stratification efforts
Wilms tumor  Cardiac toxicity: related to anthracyclines,  Cardiac toxicity: using cardioprotective agents
radiation involving heart (dexrazoxane), and minimizing chemotherapy
 Renal dysfunction: glomerular and tubular and radiation when possible
damage; end-stage renal disease in patients  Renal dysfunction: nephron-sparing surgery
with bilateral Wilms tumor or receiving for bilateral disease, avoiding nephrotoxic
radiation therapy in unilateral disease agents (for example, non-steroidal anti-
inflammatories)

some cooperative treatment protocols. Current practice pharmacogenomic analyses may reveal the need to dose
has eliminated this extra year of therapy for boys as with reduce certain medications or prompt the use of certain
modern upfront intensive treatment regimens, the risks drugs in patients demonstrating genetic factors that may
of this practice outweigh the benefits.17 Reduction or make a medicine more efficacious. As 20% of children
elimination of radiation therapy is another example of with cancer will be admitted to the hospital for the treat-
therapy modifications that can reduce late effects such as ment of an adverse drug reaction,25 this is an emerging
secondary malignancies. Recent data have demonstrated area of importance given the steady rise in patient access
that radiation therapy can be eliminated for patients to tumors and germline sequencing. Further, early pre-
with Hodgkin lymphoma that demonstrate adequate re- diction of patients whose tumors may not respond to a
sponse to chemotherapy.18 drug could help physicians consider alternatives earlier.
One example of this is response to platinum agents being
Less Toxic Treatments reduced by mutations in genes of the ERCC family of
New chemotherapy formulations aimed at maintaining DNA excision repair proteins.25
antitumor activity while reducing damage to normal tissue
are emerging. Liposomal formulations of chemotherapy, Onco-fertility
such as doxorubicin, are in various stages of preclinical Until new treatment options emerge, some side effects
testing and clinical trials. In addition to less toxic formula- are currently unavoidable, such as the likelihood of some
tions of traditional chemotherapy, immunotherapies have treatments affecting fertility. Patients experiencing life-
emerged as treatments with reduced—or different—toxicity threatening oncologic medical emergencies often do not
profiles as compared with DNA damage directed chemo- have time to undergo fertility preservation before initia-
therapies. To date, immunotherapies have been most tion of gonadotoxic treatments. Cumulative exposure to
successful in the treatment of pediatric leukemias and lym- cyclophosphamide and equivalent drugs greatly reduces
phomas, and the long-term toxicity profiles of these treat- a child’s future ability to have children.26,27 Postpubertal
ments continue to be examined.19–21 females and males have the option for pretreatment oo-
cyte or sperm cryopreservation.28 Recent advances in
Pharmacogenomics fertility preservation have emerged and provide a way to
Large sequencing efforts in pediatric oncology over the enhance chances of future fertility while still successfully
past decade have greatly enhanced understanding of treating a child’s cancer. For example, prepubertal fe-
germline alterations in children with cancer.22–24 This is males at some specialized centers now have access to re-
important not only for cancer predisposition and tumor search protocols attempting ovarian cryopreservation for
biology but also for the way in which a child’s genetic fertility preservation.29,30 Infertility can have a major im-
make-up may alter how they metabolize drugs. Such pact on an adult’s quality of life. Continued advances in

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 fertility preservation—and affordable, reliable access to sarcoma have not seen meaningful improvements in out-
fertility counseling and preservation services—have the comes in decades. For these cancers, researchers strive to
potential to significantly improve the long-term well- continue to better understand the biology of these tumors
being of children and adolescents with cancer.31 (heterogeneity, metastatic potential, immune evasion, treat-
ment resistance, and stemness—a cancer cell’s ability to
Long-term Survivorship
undergo “self-renewal and differentiation”34) and corre-
Pediatric oncology patients routinely follow-up in survivor- sponding interventions that may “move the needle” toward
ship clinics annually after completion of initial therapy and improving survival. As these cancer types are less common
undergo active disease surveillance for a number of years. than pediatric leukemias, some of the challenges in under-
Predicted side effects from therapy are monitored over standing these tumors derives from the fact that they are
time. Efforts to optimize communication with primary care relatively rare, thereby making tumor subpopulations more
pediatricians and include pediatricians as an active mem- challenging to study.
ber of the postcancer care team is a priority. Patients and
families often move or re-establish care and, therefore, ef- Risk Groups
forts have focused on establishing survivorship portals For cancers with >50% survival at diagnosis such as bone
that can “move” with the patient.32 A wealth of educational sarcomas, a logical question to ask is: what biologic fea-
information and care guidelines are also provided, www. tures make some primary tumors more aggressive than
survivorshipguidelines.org.33 Accurate and up to date com- others? Pediatric sequencing efforts have clearly demon-
munication regarding the overall health monitoring of sur- strated the genetic profiles across the spectrum of pediatric
vivors is also needed to ensure the successful transition to cancers. Tumor subsets exist and there is a clear need to
adult medicine care. Awareness and monitoring are key understand which tumor subsets are associated with infe-
components to successful management of long-term toxic- rior clinical outcomes. Aggressive tumor subtypes can then
ities for childhood cancer survivors (Fig 2). be studied to determine specific vulnerabilities, and ulti-
mately provide clues to new treatments to test in patients
BIOLOGY: UNDERSTANDING AGGRESSIVE TUMOR with aggressive tumor subtypes. Neuroblastoma is an ex-
SUBPOPULATIONS ample of a solid tumor where ALK mutations and N-Myc
An unfortunate reality of pediatric cancer is that some chil- amplification have been found to drive cancer progression
dren still do not survive. Children diagnosed with brain tu- and be associated with worse outcomes.35,36 ALK inhibitors
mors such as diffuse intrinsic pontine glioma (DIPG) and (eg, crizotinib, lorlatinib, etc) are being studied in the treat-
bone tumors such as osteosarcoma and metastatic Ewing ment of ALK mutated high risk neuroblastoma, an example

transition to adult
primary pediatrician
care

-coping
-cancer genetics
child and siblings -well child checks
-concerning survivorship care plan
symptoms or
physical exam
ndings
active survivorship
-abnormal labs or cancer therapy
imaging results surveillance clinic
child diagnosed
with cancer pediatric oncologist

additional pediatric subspecialty care

FIGURE 2
Overview of care transitions and collaborations for children with cancer. A child and their siblings (if applicable) receive primary pediatric
care. When a primary pediatrician notes abnormal symptoms, etc and a child is diagnosed with cancer, care shifts to the pediatric oncology
team. After therapy, the child with cancer transitions back to their primary pediatrician and both short- and long-term survivorship care
plans are developed.

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 of biologic understanding driving treatment change.37 Dedi- of DIPG biology and researchers hope such samples will
cated efforts for defining risk groups for bone sarcomas are start to provide clues for new therapeutic approaches.
underway. In addition to obtaining material at the time of original
diagnostic biopsies, biopsy material at the time of relapse
Disease Modeling is also invaluable. Tumors change over time and after ex-
Before any compound being tested in clinical trials, pre- posure to cytotoxic chemotherapy. Individual tumor subpo-
clinical testing is needed. Although cell lines are often pulations can develop resistance, ultimately resulting in
useful for dissecting the effects of a compound on signal- disease relapse.42,43 Historically, pediatric cancers were
ing pathways, cell lines often poorly mimic the complex- not always biopsied at the time of relapse to spare chil-
ity of the in vivo tumor microenvironment. With current dren from additional procedures. Given the need to better
preclinical models of many pediatric cancers, it is still understand relapsed disease to improve outcomes and the
challenging to predict clinical effectiveness of an agent.38 ability to participate in clinical trials, for example, the Na-
We strive to use patient derived xenografts and immuno- tional Cancer Institute-Children’s Oncology Group Pediatric
competent models of cancer and to represent tumor sub- MATCH trial (“matching” tumor alterations to possible tar-
sets in preclinical studies. Advances in the generation of geted therapy), there has been a shift in practice and to-
humanized mice (mice transplanted with human immune day, pediatric patients are more likely to be offered
cells) allows investigators to now better understand the rebiopsy at the time of suspected disease progression.44
complex relationships between the tumor and the body’s The MATCH trial has demonstrated the feasibility of identi-
immune system. Given the rise in immunotherapeutic ap- fying personalized therapeutic options for pediatric pa-
proaches to cancer treatment in the past decade, immu- tients with difficult to treat cancer.45
nocompetent modeling is a key emerging component in
studying the efficacy of specific immunotherapies.39 NOVEL THERAPIES
New treatment approaches are needed to continue to im-
Samples for Research prove upon long-term morbidity and mortality for pedi-
For rare tumors, every sample is valuable. National and in- atric patients with cancer. Examples of targeted agents
ternational efforts to enhance biospecimen banking of diffi- (antibodies, cellular therapies, kinase inhibitors, anti-
cult to treat cancers is a priority. The field continues to body-drug conjugates, etc) used in the treatment of pedi-
rely on the generosity and willingness of pediatric patients atric cancer are listed in Table 2.
and their families to participate in research studies to ad-
vance our understanding of these cancers.40 Optimizing Precision Oncology
sample storage conditions and annotation through data The goal of precision oncology is to identify drugs pre-
harmonization is an ongoing priority. For cancers such as dicted to work against tumors with specific mutations,
DIPG, biopsy samples were historically not obtained and etc. As noted above, The MATCH trial has demonstrated
diagnosis was made based on clinical or MRI findings the feasibility of identifying personalized therapeutic op-
alone. Recent advances in neurosurgical stereotactic biopsy tions for pediatric patients with difficult to treat can-
approaches now provide an opportunity for biopsy mate- cer.45 Examples of recent precision oncology success
rial from suspected DIPGs to be safely obtained.41 Such di- stories in pediatric oncology include the utilization of
agnostic biopsy material allows for a richer understanding NTRK inhibitors for rare NTRK pediatric solid tumors,

TABLE 2 Examples of Targeted Agents for the Treatment of Pediatric, Adolescent, and Young Adult Cancers
Cancer Type Example of Actionable Target35,46,47,67–73 Example Targeted Agents35,46,47,67–73
Acute lymphoblastic leukemia  Expression of CD19  Blinatumomab (CD19-CD3 bispecific T-cell engager, BiTE)
 CD19 chimeric antigen receptor (CAR) T cells
Infantile fibrosarcoma  NTRK fusion  NTRK inhibitors (larotrectinib, etc)
Neuroblastoma  High expression of GD2  Dinutuximab (monoclonal antibody against GD2)
 ALK mutation  ALK inhibitors (lorlatinib, etc)
Low grade gliomas  BRAF mutations  RAF inhibitors, pan-RAF inhibitors (tovorafenib), and MEK
inhibitors
Hodgkin lymphoma  CD30  Brentuximab vedotin (CD30 targeting antibody drug
conjugate. Chemotherapy agent linked to CD30 is
monomethyl auristatin E [MMAE])
Mature B cell lymphomas  CD20  Rituximab (CD20 chimeric antibody)
Epithelioid sarcoma  SMARCB1/INI1 mutations  Tazemetostat (EZH2 inhibitor)

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 such as infantile fibrosarcoma and RAF/MEK inhibitors ctDNA
for the treatment of low-grade gliomas in children.46–48 When tumor cells die, fragments of DNA from the tumor
cells are released into the bloodstream of the patient. This
Age of Immunotherapies circulating tumor DNA (ctDNA) can be detected in blood
Hundreds of immunotherapies for the treatment of cancer from patients with cancer52 and provides many future op-
now exist. Broadly, these therapies include engineered portunities: (1) more frequent monitoring of disease re-
cells, such as CD19 CAR-T cells for the treatment of pediat- lapse at a level that a scan may not be able to detect,
ric B-cell lymphoblastic leukemia, checkpoint inhibitors (2) reduce exposure to radiation, and (3) detect emerg-
ing resistant subpopulations of tumor cells while on
aimed at “reawakening” the body’s own immune system,
therapy. One large question that ctDNA may be able to
cytokine manipulation, and agents aimed at remodeling
help address is whether earlier detection and treatment
the tumor microenvironment. Although challenges exist in
of relapses will improve outcomes. As ctDNA monitoring
the utilization of CAR-T cells for the treatment of solid tu-
(“liquid biopsies”) is increasingly included on prospective
mors, exciting progress has been made in demonstrating
clinical trials, we will come to more fully understand the
the feasibility of CAR-T cell utilization for the treatment of potential of this technology. A recent example of the power
currently incurable pediatric cancers such as DIPG (diffuse of ctDNA was demonstrated in intermediate risk, fusion
intrinsic pontine glioma).49 Given the rapid rise in immu- negative rhabdomyosarcoma, where investigators demon-
notherapies being developed in adults, there is significant strate that the presence of ctDNA in a patient’s serum at di-
future potential in immunomanipulation for the treatment agnosis is associated with a worse outcome (statistically
of pediatric cancers. Currently, few children with cancer significant inferior event-free and overall survival).53
are treated with immunotherapies. In addition, we are
only beginning to understand the long-term side effects of Germline Findings
immunomanipulation on the health of children and adoles- In addition to tumor sequencing, germline sequencing of pe-
cents. As these data emerge, continued communication diatric patients with cancer has also increased and can com-
with general pediatricians is essential to ensure that these plement and enhance knowledge derived from tumor-only
effects are recognized and effectively addressed. sequencing.54,55 As discussed above, there may be potential
pharmacogenomic benefits of this information. Additionally,
Combination Approaches should a patient have a germline pathogenic variant in a
cancer predisposition gene discovered, cancer screening rec-
Tumors are known to be heterogeneous and develop ommendations may be suggested for the patient.56,57 We
treatment resistance, including resistance to targeted know that some children develop secondary malignancies
agents. Tumors rarely demonstrate long-term responses after their primary cancer therapy. We still do not fully un-
to single agents. Combination approaches to “attack” tu- derstand which pathogenic germline findings may increase
mors using different methods is one way to circumvent the likelihood of children developing a treatment-related
the resistance. Combining DNA damaging agents with im- secondary malignancy. Family members of children with
munotherapies and utilizing antibody-drug conjugates cancer may be referred for genetic counseling and testing
are 2 examples of emerging multimodality therapies that depending on the germline result found in the child. Many
have the potential to continue to change the landscape of variants of unknown significance are detected during germ-
pediatric cancer treatment. Immunotherapy timing (the line testing, and as more data emerge, screening and risk
delivery order of agents and/or severity of immunosup- recommendation are updated over time. It is especially im-
pression when agents are given) is especially critical portant to remember this for survivors who may not have
when adding immunotherapies to existing treatment reg- had access to germline testing when initially diagnosed or
imens. Preclinical data specifically addressing immuno- treated, as they may desire testing. If testing did occur, a re-
therapy timing is an emerging topic of great interest.50,51 examination of the interpretation of the findings may be
warranted given variant reclassifications over time. Many
children’s hospitals nationally now have cancer predisposi-
DETECTION AND MONITORING tion programs where referrals for genetic counseling and
Disease monitoring is conducted both on-therapy and af- testing are accepted both for patients with cancer and their
ter completion of initial therapy for the treatment of can- family members.58
cer in children. Child exposure to radiation, such as that
delivered by chest radiographs and CT scans, should al- ACCESS TO CARE
ways be avoided or minimized when possible. New tech- Pediatricians are well aware that inequities in access to
nologies are emerging that likely will revolutionize the care exist. Pediatric oncology is not spared from this
way tumor responses and relapses are monitored. reality.

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 DATA ON DISPARITIES diagnosed with cancer. Here, we highlighted several ways
In the United States, Black children diagnosed with can- in which innovations in drug delivery, monitoring, novel
cer continue to have inferior overall survival compared therapeutics, and access to care continue to help move the
with white children. One example of many is that lower field of pediatric oncology forward. Children with cancer
survival rates are observed among Black children with need excellent longitudinal care both during and after com-
acute myeloid leukemia when compared with non-Hispanic pletion of cancer directed therapy. Continuing to strengthen
white children.59 The reasons for this are understudied the partnership and communication between the patient’s
and multifactorial, though minority populations remain pediatric oncology team and primary care pediatrician is
underrepresented in cancer research.59 Rates of relapse essential in this mission.
among minority children and those living in poverty
also remain higher across disease groups,59 highlighting
the need for social determinants of health to be incorpo- ABBREVIATIONS
rated into treatment plans. Globally, overall survival for
ctDNA: circulating tumor DNA
children with cancer varies based on the income status
DIPG: diffuse intrinsic pontine glioma
of the country in which they reside. Issues with access
RWD: real world data
to cancer drugs, clinical trials, expert opinions for rare
tumors, supportive care measures, and advanced testing
such as tumor sequencing all contribute to the noted
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