Remarkable progress has been made in the treatment of childhood cancer
over the last half century with overall survival rising from only 4% to
over 80%.1 These improvements can be largely
attributed to the conduct of sequential clinical trials by international
cooperative groups over decades through an iterative process that builds
on successive trials. Another important result of the high participation
rate in pediatric cancer cooperative group clinical trials has been
standardization of treatment internationally. This standardization
itself can also be credited with improvements in outcomes for children
with cancer.1 However, not all childhood cancers have
experienced equal improvements, with many brain tumors continuing to
have poor outcomes.1
In the May 2023 issue of Pediatric Blood and Cancer , Trout el
al2 make an appropriate plea for required imaging in
cooperative clinical trials to be as minimally burdensome as possible
both to clinical imagers and patients. The authors outline a rational
set of points to follow in setting imaging requirements including
developing, with multidisciplinary input, guidelines that are widely
accepted, accessible and easily implemented, and not altering these
standards unnecessarily.
Ultimately, this involves a balance between allowing use of local
imaging protocols with as wide a latitude as possible and staying within
standardly available imaging capabilities, while still providing
comprehensive data needed for accurate staging and response assessments
on prospective multi-institutional clinical trials.
Imaging, as noted by Trout et al,1 is a surrogate for
treatment response. We would also emphasize that imaging is integral to
accurate disease staging at diagnosis and throughout therapy.
Improving the accuracy of disease staging is critical to improving
patient outcomes since incorrect staging, in and of itself, can result
in under or over treatment, leading to poorer survival or unnecessary
acute and long-term treatment-related sequelae, respectively.
Problematic imaging has previously been reported in retrospective
central imaging reviews.3,4 In theretrospective, centralized review of initial staging neuroimaging
in the Children’s Oncology Group (COG) A9961 trial in standard-risk
medulloblastoma, 7% (30/421) of patients were deemed ineligible due to
the presence of residual (n=15) or metastatic disease (n=15) and over
10% had inevaluable neuroimaging studies. Both groups had significantly
poorer survival than those with centrally-confirmed standard-risk
disease.3 Despite the report of this finding, recently
reported results of the successor study, COG ACNS0331, show a similar
incidence of inevaluable or ineligible staging neuroimaging studies on
retrospective review.4
This issue has become increasingly concerning and critical to address
prospectively given the greater tailoring of treatment in trials based
on this staging. For instance, in patients with favorable-risk disease
features and excellent survival outcomes, such as WNT medulloblastoma
(NCT02724579) or CNS germ cell tumor (NCT04684368), current COG trials
are evaluating treatment-reduction strategies to mitigate acute and
long-term treatment-related sequelae. In such studies,
insufficient/inadequate imaging may adversely impact therapy decisions
for an individual patient who is mis-staged at a) diagnosis and is
undertreated, or b) critical points in treatment (e.g. post induction
chemotherapy) where incorrect response assessment and/or restaging would
potentially result in inappropriate therapy decisions. In addition to
detrimental effects on individual patients, which may occur regardless
of whether a patient is treated on a therapeutic trial, inadequate
imaging can also compromise the integrity of the trial as enrollment of
ineligible or inevaluable patients or their assignment to inappropriate
therapeutic arms in multi-institutional trials that span years may
impact the results of potentially practice-changing trials.
To avoid over or undertreatment of patients, optimized and sufficient
imaging for accurate staging is critical. Determining imaging
requirements in COG clinical trials involves collaboration among
radiologists, oncologists and radiation oncologists. The goal is to
ensure imaging requirements provide adequate information to accurately
guide treatment and evaluate response while remaining within
well-established national/international imaging guidelines such as the
Response Assessment in Neuro-Oncology (RAPNO). Typically, imaging
modality, timing, anatomic coverage and need for contrast are determined
using such established imaging guidelines which are generally adopted as
standard-of-care. However, allowing “standard-of-care” imaging to be
entirely defined locally can prove problematic where sites have not
adopted such established imaging guidelines for sufficient staging and
response assessments in their routine clinical protocols. The
requirement for adequate routine clinical imaging for staging is
distinct from imaging for research and correlative studies that
consortia with appropriate mandates, site expertise and funding can
consider as secondary or exploratory objectives and may warrant site
funding.
Recognizing the breadth of the over 220 COG participating institutions
and following the principles advocated by Trout et
al,2 the COG Imaging Discipline is publishing a series
of white papers on pediatric cancer imaging, to promulgate standards of
care for tumor imaging. Notably, these MRI parameters have been designed
for implementation in routine clinical practice, as well as multi-center
clinical trials,5 and supported by conclusive data
from generations of studies over decades.3,4,6Moreover, in response to concerns about inadequate imaging and/or
misinterpretation, recent COG brain tumor trials have adopted a rapid
central imaging review with optimized MRI sequences.5The early experience of centralized imaging on the COG ACNS1422 study
for average-risk WNT medulloblastoma patients (NCT02724579), was
consistent with previous reports that approximately 10% of patients are
wrongly staged by imaging locally.7 This improved
quality control, alone, affords the opportunity to improve survival in a
subgroup of patients even without any new therapeutic interventions.
Furthermore, understanding the burden of requiring imaging that may vary
from a site’s routine and requesting repeat imaging of subjects to
ensure adequate staging, the COG has recently undertaken a proactive
survey of COG site MR brain tumor imaging protocols. Response to date
reveals variable alignment of local institutional imaging with
international, published standards. By providing individual site
feedback, we hope to make the prospective adoption of well-established
imaging guidelines more efficient. Ultimately, this approach will lead
to improved staging and treatment decision making for children with
brain tumors regardless of whether they are treated on clinical trials.
In summary, we agree with the plea by Trout et al for cooperative
clinical trial imaging to be reasonable and minimally burdensome. The
conduct of clinical trials is becoming increasingly complex, often
requiring real-time assessment of imaging by central reviewers. We, who
conduct these cooperative trials, are dependent on, and appreciative of,
local site efforts required to maintain imaging necessary to support
these advances in treatment of pediatric tumors.