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\begin{document}

\title{A Survey of 30 years of Pediatric Clinical Trial Radiotherapy Dose
Constraints}



\author[1]{April Vassantachart}%
\author[2]{Arthur Olch}%
\author[3]{Marjorie Jones}%
\author[4]{Christophe Marques}%
\author[5]{Cecile Ronckers}%
\author[6]{Louis Constine}%
\author[5]{John Maduro}%
\author[7]{Charlotte de Boer}%
\author[2]{Kenneth Wong}%
\affil[1]{Los Angeles County University of Southern California Medical Center}%
\affil[2]{University of Southern California Keck School of Medicine}%
\affil[3]{Children's Hospital Los Angeles}%
\affil[4]{Ochsner Lafayette General}%
\affil[5]{Prinses Maxima Centrum voor Kinderoncologie}%
\affil[6]{University of Rochester}%
\affil[7]{Amsterdam Universitair Medische Centra}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Radiation therapy normal tissue dose constraints are
critical when treating pediatric patients. However, there is limited
evidence supporting proposed constraints which has led to variations in
constraints over the years. In this study we identify these variations
in dose constraints within pediatric trials both in the United States
(US) and in Europe used in the past 30 years. Procedure: All pediatric
trials from the Children's Oncology Group website were queried from
inception until January 2022 and a sampling of European studies was
included. Dose constraints were identified and built into an organ-based
interactive web application with filters to display data by
organs-at-risk (OARs), protocol, start date, dose, volume, and
fractionation scheme. Dose constraints were evaluated for consistency
over time and compared between pediatric US trials and European trials
Results: One hundred and five closed trials were included---93 US trials
and 12 European trials. Thirty-eight separate OARs were found with high
dose constraint variability. Across all trials, nine organs had greater
than 10 different constraints (median 16, range 11-26), including serial
organs. When comparing US versus European dose tolerances, US
constraints were higher for seven OARs, lower for one, and identical for
five. No OARs had constraints change systematically over the last 30
years. Conclusion: Review of pediatric dose-volume constraints in
clinical trials showed substantial variability for all OARs. Continued
efforts focused on standardization of OAR dose constraints and risk
profiles are essential to increase consistency of protocol outcomes and
ultimately to reduce radiation toxicities in the pediatric population.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Survival rates in pediatric cancers continue to improve, with 5-year
survival rates ranging from 68\% to 86\% \textsuperscript{1}. However, a
consequence of improving survival outcomes is the increased long-term
morbidity of treatment toxicities \textsuperscript{2--4}. Radiation
therapy is necessary for childhood cancer types and has evolved with the
growing awareness of long-term sequelae following
treatment\textsuperscript{5}. This is of particular concern among
children and adolescents for whom irradiation of actively developing
tissues impairs growth and maturation. Accordingly, radiation exposure
can cause neurocognitive, growth, and reproductive deficits, as well as
organ dysfunction and risk of subsequent malignancies
\textsuperscript{6--12}. Modern radiation techniques, with improved
imaging modalities, comprise one such effort to reduce late adverse
effects. While these advanced techniques deliver highly uniform and
conformal dose distributions to the target volumes, incidental
irradiation of surrounding normal tissues, referred to as organs at risk
(OARs), are more variable and depend on their proximity to the target
volume, the prescribed tumor dose, the radiation technique, and the
permitted dose-volume constraints used during treatment planning
\textsuperscript{13}.

Evidence-based dose-volume risk guidelines and consensus constraints are
essential to provide optimal tumor control in a safe and effective
manner that minimizes toxicity. Clinical trials requiring radiotherapy
rely on the current state of knowledge about normal organ dose-response
to inform the choice of dose constraints in protocols. However,
organ-specific constraints specified in adult protocols have been shown
to be highly variable \textsuperscript{14}. To counter this, task forces
have formed to evaluate normal tissue tolerances and propose
corresponding dose-volume constraints, with notable collaborations being
Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC)
and Pediatric Normal Tissue Effects in the Clinic (PENTEC) in adults and
children, respectively \textsuperscript{13,15}. This study provides a
survey of the dose-volume constraints from closed clinical trials in the
Children's Oncology Group (COG) as well as others outside of the United
States (US), in an effort to describe the heterogeneity in OAR-specific
dose constraints in contemporary and historic protocols. Such variations
undermine the clinical trial paradigm of consistency and motivate an
organized effort to redefine and standardize OAR dose constraints across
clinical trials. To our knowledge, an evaluation of dose constraint
variability for pediatric trials has not been previously documented.

\textbf{Methods and Materials:}

All closed pediatric trials from the COG website (which also includes
the Pediatric Oncology Group {[}POG{]} and the Children's Cancer Group
{[}CCG{]}) were queried from inception until January 2022 (a 30-year
period) and included if radiation was used. A sampling of European
studies was included, based on international protocols actively
recruiting patients from 2016-2017 in the Netherlands. The European
trials were comprised of the International Society of Paediatric
Oncology (SIOP), European and American Osteosarcoma Studies (EURAMOS),
German Society of Pediatric Oncology and Hematology (GPOH), Dutch
Childhood Oncology Group (DCOG), EWING2008, and European Paediatric Soft
tissue sarcoma Study Group (EpSSG). Trial OAR dose constraints were
reviewed, including both conventionally fractionated constraints with
photons or protons, and radiosurgery (SRS) constraints.

Dose constraints were compared in three ways. First, graphical scatter
plot overviews of all values were created for each organ to facilitate
an overall comparison of heterogeneity. Second, for a more quantitative
comparison of high dose constraints between pediatric US and European
groups, Dmax (maximum dose) or the dose to a volume [?] 20\% was compared.
Third, specific commonly used OARs were investigated for variability in
the volume percent constraints. OAR constraint data was visualized by
building an interactive web application. This website application
renders OAR constraint data in both plot and table format based on the
pediatric group, protocol, date enrollment started, dose, volume, and
number of trials with the same constraint. Users may apply filters to
display associated data.

\textbf{Results:}

One hundred and five trials were included: 93 from the COG website
(COG/CCG/POG) and 12 protocols recruiting patients in European
countries---ten from European collaborative groups and two from national
groups (DCOG in the Netherlands and GPOH in Germany). The trials
included are listed in \textbf{Supplemental Table S5} . Most of the
protocols involved concurrent chemoradiation with chemotherapeutic
agents including vincristine, cisplatin, carboplatin, cyclophosphamide,
ifosfamide, and etoposide. Anthracyclines were frequently used but
generally not during the radiation therapy course.

Thirty-eight unique OARs were found. The number of different constraints
per OAR within the protocols varied widely, ranging from a single
constraint for the hypothalamus from COG ACNS 0222 to 29 unique kidney
constraints within 68 protocols. Other OARs with at least 10 unique
constraints included the liver, lungs, spinal cord, optic chiasm, optic
nerves, heart, brainstem, and brain at 26, 24, 20, 16, 14, 13, 11, and
11, respectively. An example of the variability of dose constraints in a
critical organ can be seen with the spinal cord constraints ranging from
a Dmax of 40 Gy up to V57 Gy \textless{} 10\% (less than 10\% of the
volume receiving 57 Gy). For several OARs, different protocols chose the
same dose metric but assigned a wide range of volumetric limits. For
example, the heart V30 Gy limit ranged from 40-100\%. For kidney, V12 Gy
was limited by some protocols to 20\% but for others, up to 100\% and
the V14.4 Gy limit ranged from 33-100\%. For kidney D50\%, constraints
ranged from 8-24 Gy. For cochlea, the allowed dose for 50\% volume
ranged from 20 Gy to 40 Gy. Further dose-volume metrics are listed
in\textbf{Table 1} . Example diagrams illustrating the range of
constraints, pediatric group, and number of trials associated with each
constraint can be seen in \textbf{Figure 1A-C} .

When comparing the high dose-volume constraints (Dmax or dose to a
volume [?] 20\%) between pediatric US constraints and European
constraints, 13 of the 38 OARs had at least two constraints with either
a Dmax or a volumetric parameter of [?] 20\%. US and European constraints
matched in five of these OARs (brain, cornea-lacrimal gland, optic
chiasm/nerves, and small-large bowel). European constraints had higher
dose allowances in one OAR (brainstem), while US constraints were higher
in seven OARs (spinal cord, bladder, heart, kidneys, lungs, liver, and
mandible), \textbf{Table 2} .

The conventionally fractionated constraints for all trials organized by
the OARs are listed in \textbf{Supplemental Table S1} with available
Pediatric Normal Tissue Effects in the Clinic (PENTEC) data listed for
comparison \textsuperscript{15--19}. PENTEC is an ongoing systematic
effort to summarize and, where feasible, suggest OAR-based constraints
for children and adolescents based on published
evidence\textsuperscript{15}. Four protocols addressed proton
constraints (an additional 3 trials that are currently active were not
included) and three trials included SRS constraints (an additional 2
trials currently active were not included) listed in
\textbf{Supplemental Table S2 and S3} . Additionally, the interactive
web application URL is also available in \textbf{Supplemental Data S4} .
To account for changes in constraints over time, we included within the
web application the option to filter by start date of the protocol.
Although much has changed technologically over the past 30 years,
radiotherapy dose constraints generally did not show any consistent
pattern of change over time for any of the OARs including the spinal
cord, brainstem, optic apparatus, lungs, heart, and kidneys.

\textbf{Discussion:}

In our review of 105 pediatric trials, there was substantial variability
in recommended dose-volume constraints among all OARs. While
heterogeneity is present in adult clinical trials, many protocols refer
to pre-existing OAR guidelines from QUANTEC, the American Association of
Physicists in Medicine Task Group (AAPM-TG) 101, and Hypofractionated
Treatment Effects in the Clinic (HyTEC) \textsuperscript{13,20,21}. A
comparable pediatric consensus guideline was not previously available,
although it is well known that late effects in normal tissues vary
across the age spectrum and can lead to devastating
consequences\textsuperscript{6}. It is reassuring that the current
PENTEC guidelines are now being developed and will help promote more
consistency among recommended dose constraints across protocols.

To a certain extent, the degree of variability can be justified by
different treatment goals for various cancer histopathologies, target
volumes, sex, age, and the use of concomitant treatments. That is, the
accepted normal tissue risk tolerance for some diagnoses might be
greater if their curability is less likely. Nevertheless, consistency in
constraints was poor even for the same diagnosis, chance for survival,
or similar exposures to chemotherapy. For serial structures such as the
spinal cord, optic chiasm, and optic nerves, reduced variability between
dose constraints would be expected for a Dmax constraint compared to
volumetric constraints. However, this was not seen with 20, 16, and 14
unique constraints across the trials for these three structures,
respectively. When comparing pediatric US constraints to European
constraints, constraint tolerances were higher for parallel organs
including the bladder, heart, lungs, liver, and kidneys. For serial
structures, dose tolerances were mixed with the COG protocols allowing
for a higher dose for the spinal cord, but a lower dose for the
brainstem.

One might expect dose constraints to change over time, consistent with
new normal organ dose-response data becoming available. However, none of
the OARs had a systematic pattern of change in protocol dose constraint
values over time to indicate an increase or decrease in the tolerated
dose. Rather, the variations were either in choice of the dose-volume
pairing or non-systematic changes, neither of which indicated the
influence of new information but are more likely due to a lack of both
good dose-response data and consensus by protocol committee members.
Additionally, review of the currently active protocols also show
constraints were consistent with previous trials with no consistent
pattern of change. This finding further highlights the need for more
evidence-based, consistent constraints across protocols.

It is provocative to speculate on the reasons for the observed
heterogeneity in constraints across protocols or even continents.
Presumably, the scientific investigations used to derive constraints are
available to clinicians internationally. In addition, we would not
expect any cultural differences in the degree of tolerance for adverse
outcomes. It would be interesting to collate dose constraints from other
continents and compare these with the U.S. and European values
identified. It would be even more nuanced to compare constraints within
specific countries in these continents. To date, none of the cited
constraints were derived from a stringent formal process as is customary
in clinical guideline development, which likely contributed to the
observed heterogeneity. This observation was mirrored in the setting of
recommendations for risk-based surveillance among childhood cancer
survivors, for which substantial international variation was
demonstrated, and acted upon, with the inception of the International
Guideline Harmonization Group (IGHG)\textsuperscript{22}. Additionally,
consensus is lacking for dose-volume constraints for protons and SRS
with mentions of these constraints in seven and five trials,
respectively -- when including currently active trails. We encourage the
PENTEC task group and future task groups to evaluate both modalities as
there is little consensus on proton constraints, and also an increasing
number of trials using SRS and stereotactic body radiotherapy (SBRT) to
ablate metastatic disease.

Recently, five PENTEC reviews have been published on the rates of
neurocognitive effects and brain necrosis, breast hypoplasia and
impaired lactation, primary hypothyroidism, pulmonary injury, and
salivary and dental complications for childhood cancer survivors treated
with radiotherapy \textsuperscript{16,17,19,23,24}. The model for a 5\%
risk of subsequent IQ \textless{} 85 suggested constraints stricter than
the current pediatric protocols while the Dmax constraints related to
necrosis were similar in these protocols to the recommended PENTEC
constraints (\textbf{Supplemental Table S1} ) \textsuperscript{18}. The
PENTEC dose-toxicity data regarding salivary function demonstrated a
13-32\% risk of acute and chronic grade \selectlanguage{ngerman}³ 2 xerostomia with a mean
parotid dose of 35-40 Gy \textsuperscript{19}. Within our review of
current and active trials, parotid constraints were more restricted
ranging from V20 \textless{} 25\% to V34 \textless{} 50\%, and a
solitary Dmax constraint of 40 Gy. Breast and thyroid constraints were
not presented in our reviewed protocols for comparison with the PENTEC
data and additional OAR publications are highly anticipated.

To our knowledge, this is the first study to provide a survey of
radiotherapy dose constraints within a broad range of pediatric clinical
trials. Our intentions were to describe the current landscape of
OAR-specific dose constraints, display a comprehensive guide and
interactive website for pediatric constraints used on trials, and
present the high variability and inconsistencies within these trials to
continue to promote the interest and support for task groups to
establish quantitative, evidence-based dose-volume risk guidelines for
radiation therapy in childhood cancers.

\textbf{Conclusion}

Review of pediatric dose-volume constraints in clinical trials showed
substantial variability for all OARs, both for US trials and for
European relative to US trials. None of the OARs had constraints
systematically change over time, indicating that the variations seen
were not due to the application of new dose-response information, but
more likely due to a lack of both robust dose-response data and
consensus by protocol committee members who establish the constraints.
Continued efforts focused on standardization of OAR dose constraints and
risk profiles are essential to increase consistency of protocol outcomes
and ultimately to reduce radiation toxicities in the pediatric
population.

\textbf{Conflict of Interest Statement}

Cecile Ronckers has a Dutch Cancer Society Grant for Jr Group Leaders --
grant \#UVA2012-5517. 2013-2018. Marjorie Jones contributed to this
research project within the USC/CHLA Summer Oncology Research Fellowship
Program, supported by a National Cancer Institute R25 grant CA225513,
the Norris Comprehensive Cancer Center, Children's Hospital Los Angeles,
Concern Foundation for Cancer Research, and Tri Delta. Louis S. Constine
has grants/contracts from the University of Alabama for COG Survivorship
Guidelines, has royalties/licenses with Up-to-date, Springer, and
Wolters Kluwer, has honoraria for the American Society for Hematology
and the University of Miami Radiation Oncology Grand Rounds, and
participates on the Pediatric Oncology Board. All other authors have no
conflicts of interest.

\textbf{Figure number and legend}

Figure 1. Representative plots of the A) spinal cord B) brainstem and C)
optic chiasm constraints based on the number of trials and treatment
modality

\textbf{Data Sharing Statement}

The data that supports the findings of this study are available in the
supplementary material of this article.

\par\null

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