Pediatric oncology in 2023 is a study in contrasts. Decades of
multi-institutional clinical trials have led to dramatic increases in
five-year survival rates across broad categories of childhood cancers.
The number of survivors of childhood cancer continues to increase,
estimated to be 500,000 in the United States as of
2020.1 The genomic landscape of most pediatric
malignancies has been defined through comprehensive sequencing projects,
leading to refinements in risk stratification and identification of more
specific targets for potential therapeutic intervention. Precision
treatment, beyond traditional cytotoxic chemotherapy, radiation, and
surgery, has become a reality for some pediatric cancers. Regulatory
changes have provided significant incentives to pharmaceutical companies
to include children in clinical trial research with innovative
therapies.
However, each of these modern-day successes widens the gulf between
challenges that remain. Improvements in outcome have not been uniform
across all malignancies. The impressive gains seen in acute
lymphoblastic leukemia and Hodgkin lymphoma stand in stark contrast to
the absolute lack of progress in metastatic sarcomas and diffuse
intrinsic pontine glioma. Although five-year survival is a convenient
benchmark, its use obscures two important issues. First, five-year
survival is not the same as ten- or twenty-year
survival.2 Too many five-year pediatric cancer
survivors will still succumb to their primary malignancy. Second, early
survival is not without cost. Standard treatments carry a substantial
burden of acute and chronic severe and potentially fatal complications,
including accelerated cardiovascular disease, endocrinopathies, stroke,
and secondary malignancies.3 The overall spectrum of
late effects has not changed for most childhood cancer survivors because
our most common treatment approaches have not changed substantially from
those used in the 1970s. Despite its potential, precision treatment has
not replaced cytotoxic chemotherapy and radiation for most pediatric
cancers. Even more fundamental, clinical tumor sequencing to guide
diagnosis and refine treatment is not broadly available to all children
with cancer, especially at initial diagnosis. Finally, the economics of
drug development drives much of the pharmaceutical industry’s focus on
targets relevant to the common carcinomas seen in adults rather than the
less common alterations seen in leukemias and embryonal solid tumors
seen in children.
In 2023, the Children’s Oncology Group (COG) is poised to play a pivotal
role to build upon the prior achievements in pediatric oncology and
address the remaining challenges. Formed in 2000 by the merger of four
legacy pediatric cancer cooperative groups, COG is the National Cancer
Institute’s clinical trials organization devoted to childhood,
adolescent, and young adult cancers. Since 2000, COG has conducted over
330 clinical trials for common and rare pediatric malignancies. With a
centralized biorepository, COG facilitates the collection, storage, and
distribution of >100,000 biospecimens annually from
clinical trial participants and non-study biobanking. With more than 220
member institutions in the United States, Canada, Australia, New
Zealand, and Saudi Arabia, the vast majority of children with cancer in
these countries are treated at a COG site. Given the relative rarity of
pediatric cancer, multi-institutional collaboration is essential to the
timely conduct of research and COG is uniquely positioned to do this in
many pediatric and adolescent/young adult cancers.
To summarize COG’s recent achievement and outline our plans for the
future, COG’s scientific committees are publishing their Blueprints in
this special issue of Pediatric Blood and Cancer . Similar to the
2013 Blueprints, these summaries outline how COG will address the
remaining challenges in pediatric oncology. Each Blueprint describes the
priorities that the COG committees will pursue to improve outcomes for
children with cancer by improving survival rates, reducing short- and
long-term morbidity from treatment, improving our understanding of
cancer biology, seeking to identify and reduce health disparities, and
further identifying the causes of childhood cancer.
Although it was reported that 71% of children with cancer participated
in front-line cooperative group trials in 1991-1994,4study enrollment fell to 26% in 2000-20035 and 20%
in 2004-2015.6 In a resource-constrained environment,
it is not feasible to offer clinical trials for all cancer types.
Instead, COG is focusing its trials on malignancies for which the
survival rate remains sub-optimal, including acute myelogenous leukemia,
high-risk neuroblastoma, high-grade gliomas, and metastatic sarcomas. In
addition, malignancies with a relatively high early survival rate but
with a substantial burden of short-term and late effects (including
Hodgkin lymphoma, medulloblastoma, localized sarcomas, and acute
lymphoblastic leukemia) will be prioritized for clinical trials with the
intent to reduce the negative impact of theraph without compromising
high cure rates.
Since the majority of children with cancer do not now participate in
front-line clinical trials, it is also essential to gather information
and biospecimens from children who are not part of clinical trials.
Project:EveryChild, COG’s overarching registry and biobanking study, was
launched in 2015 to capture valuable information and specimens from all
children with cancer, not just those who enroll on clinical trials.
Project:EveryChild replaced disease-specific biology studies to
streamline data and specimen collection. It also includes optional
consent for future contact, which has facilitated the conduct of
multiple epidemiology studies through COG. As of 2022, over 44,000
children have enrolled on Project:EveryChild and more than 250,000
biospecimens have been collected. With the planned addition of
neuroblastoma and renal tumors, Project:EveryChild will provide a
unified mechanism for registration, data collection, biobanking, and
consent for future contact for all pediatric cancers.
Project:EveryChild also provided an efficient platform to launch the
Childhood Cancer Data Initiative (CCDI) Molecular Characterization
Initiative (MCI) in March 2022.7 To address the
unequal access to molecular testing at diagnosis, MCI is open to
children, adolescents, and young adults with newly diagnosed central
nervous system tumors, soft tissue sarcomas, and selected rare tumors.
Consent for MCI participation is obtained at the time of enrollment on
Project:EveryChild, including collection of tumor and blood samples.
Using COG’s centralized biobank for tissue processing, MCI provides
whole exome sequencing of tumor and blood, panel RNA sequencing of
tumor, and tumor methylation classification (for central nervous system
tumors only) in clinical reports returned to the treating institution
within 14 days of receipt of material. MCI’s comprehensive molecular
reports may then be used to help refine a participant’s diagnosis and
may suggest specific treatment options. In addition, complete sequencing
data are being transferred regularly to a publicly available storage
site along with clinical annotation from COG. CCDI anticipates these
data will be used for new discovery in the research community. Perhaps
most importantly, MCI provides equitable access to comprehensive genomic
sequencing of tumor and germline results regardless of where a child
with cancer receives care across the COG network. As more molecularly
targeted therapies become available, the value of comprehensive tumor
sequencing will become even more apparent, and frankly necessary.
Historically, evaluation of novel agents in children was avoided or an
afterthought, as evidenced by the median delay of 6.5 years between
first testing of cancer drug in adults and the first testing in
children, even when restricted to agents that were ultimate approved by
the Food and Drug Administration (FDA).8 Collaboration
with the pharmaceutical industry is a key feature to COG’s overarching
strategy to improve outcomes. Over the past twenty years, data from COG
studies have been used to obtain a pediatric labeling indication from
the FDA for 15 agents in 19 diseases or molecular contexts (Table 1).
Although four of these studies were conducted with regulatory intent,
most were not designed with a plan for an FDA filing. Nonetheless, the
reliability of COG institutions and data quality were sufficient to
support regulatory approval. The full implementation of the Research to
Accelerate Cures and Equity (RACE) for Children Act in 2020 sought to
increase pediatric investigations by providing a regulatory requirement
to include children in cancer clinical trials for agents that target a
pathway of relevance in pediatric cancer.9 In the
post-RACE regulatory world, COG hopes to be viewed as the pediatric
cancer clinical trial organization of choice by pharmaceutical partners.
To improve the outcomes for children with cancer, it is essential to
ensure that success is experienced by all children with cancer
regardless of social factors. Unfortunately, there are disparities in
cancer outcome among children based upon race or ethnicity,
socioeconomic factors, and proximity to a treatment center specializing
in childhood cancer. Compared with incidence data from Surveillance,
Epidemiology, and End Results Program, enrollment on front-line clinical
trials6 and COG’s molecularly-matched treatment study
(Pediatric MATCH)10 mirror the racial and ethnic
demography of the general pediatric oncology population, suggesting
relative equity of access to clinical trials within the COG network.
However, COG studies have demonstrated disparities of outcome within
individual treatment studies11 and within a single
disease group across multiple treatment studies.12 We
have also observed disparities in the lost-to-follow-up rate on our
clinical trials.13 Therefore, participation on a
clinical trial is not sufficient to mitigate disparities in outcome or
to maintain study retention. For these reasons, COG is committed to
promoting diversity in study participation,14documenting outcome disparities when they occur, identifying the
etiology of compromised social determinants of health, and developing
interventions to eliminate disparities in access to treatment and in
cancer outcomes.
The future challenges in pediatric oncology are daunting, but pediatric
oncologists, pediatric oncology nurses, radiation oncologists, surgeons,
pharmacists, and caregivers are inherently optimistic. Furthermore, the
magnitude of a challenge can drive innovation. For example, the rarity
of pediatric cancer necessitates multi-institutional and sometimes
multi-natiohnal collaboration to a degree not experienced in any other
field of medicine. The scope of the COG network allows us to test
interventions on a near population scale, leading to broad adoption if
successful. The strategies outlined in these COG Blueprints represent
multi-disciplinaries plans to address our most vexing problems. Working
together, we will improve the outcomes for children, adolescents, and
young adults with cancer by restoring them to long-term health.
Table 1: Medications with Food and Drug Administration approved
indication for children using data from COG clinical trial. Studies that
received financial support from a pharmaceutical company are underlined.
Studies that were fully funded by industry partners without support from
the National Cancer Institute and developed with the intent for
regulatory filing are in italics .