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).