Challenging knowledge gaps
For future progress, HARMONICA envisages to collaborate through
multidisciplinary activities on the levels of discipline groups and
panels. This organized collaborative structure for transatlantic experts
from COG-RTC and SIOP-RTSG aims to optimize progress for children with
renal tumors. Most important is to attract relevant stakeholders
including policy makers, parents and long-term survivors but also
funding agencies. This will allow attainment of knowledge and
achievement of goals by involving, recruiting, and exchanging talented
students and young investigators, and by including LMICs as partners,
for developing curative strategies. All this will further enhance access
of care for each child with renal cancer worldwide, which is also a goal
of SIOP and WHO. In effort to expedite such collaboration, we have
identified areas of research that could benefit from international
dialogue and collaboration and are the subject of a series of the 10
manuscripts that follow, each first authored by young investigators that
bring new ideas and fresh perspective into the field of pediatric renal
cancer. Briefly, the major themes explored in each of these manuscripts
is described below.
Epidemiological challenges, addressed by Libes et al, are not limited to
distinct database processes and definitions between the cooperative
groups and within the various LIMIC countries. Opportunities from
improved diagnostics, biobanking and integration of molecular testing
are discussed, as is the advantages of improved central review of
pathology and imaging. A global registration and data sharing initiative
concept is introduced.
Understanding the challenging definitions of nephrogenic rests
pathologically and radiographically, as well as nephroblastomatosis are
critical first steps before data sharing or comparative clinical trial
data can be advanced, is discussed by Fialkowski et al. Somewhat
related, Welter et al. address the pathophysiology of bilateral and
multifocal Wilms tumor and review renal tumor epigenetic and genetic
predisposition syndromes. Correlating biology with clinical parameters
including chemoresponse and survival outcomes including organ function
are likely to benefit from such ongoing international collaboration.
The field of tumor biomarkers, tumor heterogeneity, and the application
of liquid biopsy is tackled by Walz et al., wherein targeted
pre-clinical research and data sharing is highlighted as future
opportunities to ultimately inform treatment strategies and impact
patient outcomes. Hont et al. subsequently review key translational
aspects of pediatric renal tumor microenvironment and considerations for
potential immunotherapy.
Various similarities and controversies in renal tumor imaging between
the COG and SIOP are addressed by van der Beek et al. Future innovative
technologies and concepts, amenable to study optimally through
intergroup collaboration, are highlighted. Anatomic considerations are
further explored by Tracy et al. and a surgeon-oriented but
multidisciplinary group of authors wherein they share consensus opinions
regarding the limitations of partial nephrectomy and controversies
surrounding the approach to intravascular tumor extension. Technical
advances in the surgical management of Wilms tumor, focusing on future
directions and controversy of minimally invasive surgery, image guided
surgery and fluorescence-guided surgery, and optimization of the
surgical approach to lymph nodes are discussed by Romao et al.
Analogously, McAleer et al. review the consensus, controversies and
future directions of radiotherapy for Wilms tumor, noting knowledge gaps
and opportunities for future research in the areas of advanced
radiotherapy technologies including IMRT and proton beam therapy, the
impact of molecular markers on RT indications, mitigation of reduced
fertility through modulated radiation approaches, and promotion of
radiotherapy late effects research, much of which can be more optimally
advanced through international efforts.
In the final manuscript, Ortiz et al. address advances in the clinical
management of high-risk Wilms tumor. The shifting definition of ‘high
risk’ and which patients that includes is addressed, accounting for
shifting outcomes and limited resources that can impact outcomes
greatly. Advancements in laboratory (biology, tumor model, drug
screening) and early phase clinical trials focusing on patients with
pediatric renal tumors is emphasized.
It is acknowledged that a key limitation of intergroup collaboration is
the discrepant upfront approach to patient management. The preferred
approach of randomized trials to address key advances is a challenge to
pursue via intergroup collaboration because of such global differences
in upfront treatment approaches. Regulatory and pharmaceutical industry
challenges are also present, especially for new agent trials, when
international multi-group smaller (patient number) trials are being
considered. Strategies may be available, however, to overcome these
potential barriers. For example, the COG RTC and SIOP RTSG also convened
to propose a similar chemotherapeutic backbone for children with
rhabdoid tumor, upon which different biologics would be added by the
different cooperative groups, obviating the need for complex new drug
trials combining cooperative groups, but enabling comparison of outcome
data. Through sharing of ideas, data, and research on an international
level, efforts like HARMONICA hold promise to move the pediatric renal
tumor field in the direction that benefits all children with renal
tumors globally. Nevertheless, access to such high-tech innovations and
molecular driven personalized treatment developments including advanced
and novel surgical and radiotherapeutic techniques need to be enhanced
in Low- and Middle-Income Countries (LMICs).