Progress by international collaboration for pediatric renal tumors by HARMONIzation and COllaboration: The HARMONICA initiative
2022; Wiley; Volume: 70; Issue: S2 Linguagem: Inglês
10.1002/pbc.30082
ISSN1545-5017
AutoresMarry M. van den Heuvel‐Eibrink, Conrad V. Fernandez, Norbert Graf, James I. Geller,
Tópico(s)Pediatric Urology and Nephrology Studies
ResumoPediatric Blood & CancerVolume 70, Issue S2 e30082 EDITORIALFree Access Progress by international collaboration for pediatric renal tumors by HARMONIzation and COllaboration: The HARMONICA initiative M. M. van den Heuvel-Eibrink, M. M. van den Heuvel-Eibrink Princess Máxima Center for Pediatric Oncology, Utrecht, The NetherlandsSearch for more papers by this authorC. V. Fernandez, C. V. Fernandez IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, CanadaSearch for more papers by this authorN. Graf, N. Graf Saarland University, Homburg, GermanySearch for more papers by this authorJames I. Geller, Corresponding Author James I. Geller [email protected] orcid.org/0000-0001-5181-116X Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA Correspondence James Geller, 3333 Burnett Ave, Cincinnati, OH, USA. Email: [email protected]Search for more papers by this author M. M. van den Heuvel-Eibrink, M. M. van den Heuvel-Eibrink Princess Máxima Center for Pediatric Oncology, Utrecht, The NetherlandsSearch for more papers by this authorC. V. Fernandez, C. V. Fernandez IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, CanadaSearch for more papers by this authorN. Graf, N. Graf Saarland University, Homburg, GermanySearch for more papers by this authorJames I. Geller, Corresponding Author James I. Geller [email protected] orcid.org/0000-0001-5181-116X Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA Correspondence James Geller, 3333 Burnett Ave, Cincinnati, OH, USA. Email: [email protected]Search for more papers by this author First published: 24 November 2022 https://doi.org/10.1002/pbc.30082AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Since the initial attempts to treat children with renal cancer over 50 years ago, outcome for children with renal cancer has generally become promising. While the first endeavors mainly included surgical treatment, in the early 1960s radiotherapy and chemotherapy were introduced, leading to cure of patients, including some with metastatic disease.1 Since then, overall survival rates for the most common type of renal tumors in childhood (nephroblastoma or Wilms tumor [WT]) have improved to more than 90%. These excellent treatment outcomes are similar in the two largest clinical trial groups (the Children's Oncology Group Renal Tumor Committee (COG-RTC; former National Wilms Tumor Study Group [NWTSG], and the International Society of Pediatric Oncology Renal Tumor Study Group [SIOP-RTSG]). Despite the difference in upfront treatment choice (primary surgery when feasible [COG-RTC] or preoperative chemotherapy [SIOP-RTSG]), both groups have optimized the stratification of patients in their trials by modifying the intensity of treatment according to individual risk factors, in order to improve outcome for high-risk renal tumor types, but also to reduce early and late toxicity in lower and intermediate-risk tumors as much as possible.2-4 This improvement in risk stratification has resulted in better outcomes and less cancer-related toxicity. However, for remaining small subgroups of pediatric renal tumor patients with very poor outcomes, further understanding of the underlying biology, in correlation with clinico-pathological characteristics, is an unmet need. Further, standard multidisciplinary treatment (surgery, radiotherapy, chemotherapy) can be challenging to access and/or deliver in some low- and middle-income countries (LMIC). The power inherent in international collaboration to address these challenges was a driving principle that supported the creation of the HARMONICA (HARMONIzation and COllaboration) initiative in 2015, when we established an organized collaborative structure for trans-Atlantic experts from COG-RTC and SIOP-RTSG. The mandate of HARMONICA is to identify specific challenges for pediatric renal tumor subsets in order to meet the aims of our global approach to cure every child with a renal tumor with limited toxicity. The HARMONICA group meets at least once a month by videoconferences, and as much as possible also face to face, at least once or twice a year, during existing pediatric cancer conferences. In addition, several trans-Atlantic HARMONICA expert subgroups are collaborating on specific topics. All work is currently done by a tremendous engagement of many enthusiastic members of both study groups. Despite the fact of obvious advantages, HARMONICA is still lacking funding and needs to optimize their structure as a legal entity. Notwithstanding such limitations, in this special issue of Pediatric Blood & Cancer (PBC), we present the achievements, the challenges, and the future perspectives, identified by these expert groups. 1 ACHIEVEMENTS THROUGH INTERNATIONAL COLLABORATION IN PEDIATRIC RENAL TUMORS Over the past decades, a focus on collaboration, rather than on differences in approach, has opened the door for SIOP-RTSG and COG-RTC to make translational steps on a global level toward better care. An article of Giulio D'Angio, one of the pioneers in pediatric oncology, addressed the question of pre- or postoperative therapy for Wilms’ tumor in 2008, when he wrote: “SIOP participants, their North American colleagues, and other investigators have conducted this debate in a thoroughly collegial manner. Members of any study are welcome to attend meetings of other groups, where advice and data are willingly interchanged. The children have been the beneficiaries, as they should be.”5 It was again Giulio D'Angio, who stated that “the investigators have achieved what political and religious leaders have not accomplished so far,”6 after the very first joint publication, in which datasets of children with renal tumors up to the age of 6 months were merged illustrating the benefits of such a collaborative endeavor7 Table 1. These early efforts led to a global “surgery first” consensus for such young infants. A collaborative consensus guideline for the management of adult WT was developed as well,8 as was a meta-analysis on the potential role of high-dose chemotherapy with stem cell rescue for relapse WT.9 Targeting the IGF pathways was summarized as a collaborate effort resulting from the SIOP/COG ENCCA conference.10 Intergroup mentoring of young investigators in the field of molecular genetics of WT and clear cell sarcoma of the kidney (CCSK) revealed the molecular landscape of diffuse anaplastic Wilms tumor (DAWT), favorable histology Wilms tumor (FHWT), and CCSK through the TARGET (therapeutically applicable research to generate effective treatments) initiative.11-14 TABLE 1. Select early international collaborations and HARMONIca efforts References Subject Type of manuscript Conclusions/advises based on evidence/consensus van den Heuvel-Eibrink 7 Infant Wilms tumor (WT) Meta-analysis and consensus Advice is provided to treat children ≤6 months with primary surgery, worldwide Segers 8 Adult WT Literature review and consensus Advise is provided to use (intensified) pediatric WT treatment in adults; rapid pathology review by pediatric renal tumor expert is encouraged Ha 9 High-dose chemotherapy in recurrent WT Review/perspective In general, the role of high-dose chemotherapy in children with relapsed WT is uncertain Maschietto 10 Insulin growth factor (IGF) pathway in WT Workshop report Data supporting investigation of targeting the IGF pathway and the use of demethylation agents alone or in combination with other drugs is provided in treatment of WT Dome 3 International collaboration progress in WT Review/perspective Opportunities are highlighted via coordinated expansion of international collaboration in clinical trial and laboratory science Ooms 11 Diffuse anaplastic Wilms tumor (DAWT) TARGET (therapeutically applicable research to generate effective treatments) study P53 mutations in DAWT patients is discussed Walz 12 Favorable histology Wilms tumor (FHWT) TARGET study Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in FHWT are identified and discussed Gadd 13 FHWT TARGET study Overview of molecular findings in FHWT are presented Gooskens 14 Clear cell sarcoma of the kidney (CCSK) TARGET study TCF21 hypermethylation regulates CCSK development Brok 15 Surveillance for WT Parallel surveillance consensus guideline based on data analysis Planned surveillance catches >2/3 of all WT relapses Mullen 16 Surveillance for WT x-Ray and Ultrasound may be sufficient surveillance for children with FHWT off therapy Fajardo 17 Stage 1 DAWT Parallel surveillance consensus guideline based on data analysis RT is advised in WT patients treated with upfront surgery Daw 18 Stage 1 DAWT RT is not of extra value in WT cases treated with pre-op chemotherapy Ehrlich 19 Wilms tumor, aniridia, and growth delay (WAGR) and WT Parallel evaluation of WT in setting of WAGR and other WT predisposition conditions A standardized approach of preoperative chemotherapy, surgery within 12 weeks, and histology-based postoperative chemotherapy add to excellent outcome Hol 20 WAGR and WT Review WAGR patients more often have bilateral WT tumor and rarely have metastases or anaplasia Brok 21 Unmet needs for relapsed or refractory WT Perspectives paper Relapsed WTs should undergo molecular characterization and search for actionable agents, through preclinical models and compound testing Brok 22 Phase 1 and 2 studies in WT Review/perspective Improvements to optimize the search for novel agents and recruitment to early-phase trials are needed Gooskens 23 Congenital mesoblastic nephroma (CMN) Review CMNs are usually benign, but with recurrent molecular aberrations and occasional relapse/progression van der Beek 24 Renal cell carcinoma (RCC) Review Pediatric RCC is rare. MiT-RCC and papillary type RCC represent the largest subgroup. Global collaboration is necessary to improve outcome for metastatic and relapsed pediatric RCC Spreafico 25 Wilms tumor primer in nature Review A broad overview of WT is provided with international perspectives included van der Perk 26 Gonadal damage after WT Review Risk of gonadal damage in WT patients depends on dose of alkylating agents and use of whole abdominal radiotherapy More recently, during the HARMONICA era, coordinated parallel manuscript/research efforts from COG/SIOP have focused on imaging surveillance,15, 16 stage 1 DAWT,17, 18 and WAGR (Wilms tumor, aniridia, and growth delay) and WT.19, 20 Collaborative reviews on unmet needs in WT,21 addressing international progress in WT,3 WT phase 1 and 2 studies,22 congenital mesoblastic nephroma,23 renal cell carcinoma,24 WT broadly,25 and more recently a comprehensive position paper on oncofertility issues pertinent to pediatric renal cancer26 have been finalized. Since the onset of HARMONICA, clinical outputs from such international collaboration have produced practice changes in both cooperative groups. The COG has adopted postchemotherapy histology in patients with bilateral WT who undergo delayed nephrectomy, using postchemotherapy histologic risk criteria defined by SIOP. The SIOP has adopted the COG approach to defining lung metastases and select abdominal radiotherapy dosing guidelines for CCSK. Both groups have adopted a harmonized definition to relapsed Wilms risk classification, based on upfront treatment intensity and histologic risk criteria. Such advances only touch the surface of what is possible through data sharing and meaningful open communication and dialog. 2 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 trans-Atlantic experts from COG-RTC and SIOP-RTSG aims to optimize progress for children with renal tumors. Most important is to attract relevant stakeholders including policymakers, 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 World Health Organization. In an effort to expedite such collaboration, we have identified areas of research that could benefit from international dialog and collaboration and are the subject of a series of the 10 manuscripts that follow, each first-authored by young investigators who 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 advantage 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 WT 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 preclinical research and data sharing are 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 WT, 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 WT, noting knowledge gaps and opportunities for future research in the areas of advanced radiotherapy technologies, including intensity-modulated radiotherapy (IMRT) and proton beam therapy, the impact of molecular markers on radiation therapy 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 WT. 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 multigroup 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 LMICs. ACKNOWLEDGMENTS We acknowledge all the authors from both the SIOP and COG renal committees, and guests, for their collaborative spirit in drafting the manuscripts in this issue. REFERENCES 1Graf N, Bergeron C, Brok J, et al. Fifty years of clinical and research studies for childhood renal tumors within the International Society of Pediatric Oncology (SIOP). Ann Oncol. 2021; 32: 1327- 1331. https://doi.org/10.1016/j.annonc.2021.08.1749 2Dome Jeff S, Perlman Elizabeth J, Graf N. Risk stratification for wilms tumor: current approach and future directions. 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A report of SIOP-RTSG, AIEOP, JWiTS, and UKCCSG. Pediatr Blood Cancer. 2020; 67(2):e28039. 18Daw NC, Chi YY, Kim Y, et al. Treatment of stage I anaplastic Wilms' tumour: a report from the Children's Oncology Group AREN0321 study. Eur J Cancer. 2019; 118: 58- 66. 19Ehrlich PF, Chi YY, Chintagumpala MM, et al. Results of treatment for patients with multicentric or bilaterally predisposed unilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Cancer. 2020; 126(15): 3516- 3525. 20Hol JA, Jongmans MCJ, Sudour-Bonnange H, et al. Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: the 30-year SIOP-RTSG experience. Cancer. 2021; 127(4): 628- 638. 21Brok J, Mavinkurve-Groothuis AMC, Drost J, et al. Unmet needs for relapsed or refractory Wilms tumour: mapping the molecular features, exploring organoids and designing early phase trials - a collaborative SIOP-RTSG, COG and ITCC session at the first SIOPE meeting. Eur J Cancer. 2021; 144: 113- 122. 22Brok J, Pritchard-Jones K, Geller JI, Spreafico F. Review of phase I and II trials for Wilms' tumour - can we optimise the search for novel agents? Eur J Cancer. 2017; 79: 205- 213. 23Gooskens SL, Houwing ME, Vujanic GM, et al. Congenital mesoblastic nephroma 50 years after its recognition: a narrative review. Pediatr Blood Cancer. 2017; 64(7):e26437. 24van der Beek JN, Geller JI, de Krijger RR, et al. Characteristics and outcome of children with renal cell carcinoma: a narrative review. Cancers (Basel). 2020; 12(7): 1776. 25Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021; 7(1): 75. 26van der Perk MEM, Cost NG, Bos AME, et al. White paper: oncofertility in pediatric patients with Wilms tumor. Int J Cancer. 2022; 151(6): 843- 858. Volume70, IssueS2Supplement: Pediatric Renal Tumors ‐ A HARMONICA InitiativeMay 2023e30082 ReferencesRelatedInformation
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