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) 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 consequences6. 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)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 16,17,19,23,24. The model for a 5%
risk of subsequent IQ < 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 (Supplemental Table S1 ) 18. The
PENTEC dose-toxicity data regarding salivary function demonstrated a
13-32% risk of acute and chronic grade ³ 2 xerostomia with a mean
parotid dose of 35-40 Gy 19. Within our review of
current and active trials, parotid constraints were more restricted
ranging from V20 < 25% to V34 < 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.