**16. Conclusions and future directions**

The cure rates of WT patients following multimodality therapy including RT are excellent. However, RT is an important cause of late toxicity. Novel RT techniques such as IMRT for abdominal and lung RT and proton therapy are currently being studied in SIOP and COG in prospective clinical trials and may reduce the incidence of late toxicity. Currently WT biomarkers are only utilized for defining high-risk tumors to be treated with chemotherapy. Their utilization for potentially refining indications for RT in certain risk groups remains to be studied. Detailed studies of late toxicities specifically by analyzing the effects of RT doses to target organs is critical to improve our understanding of the relationship between RT and a variety of toxicities such as infertility, hypogonadism, congestive heart failure and secondary malignancies [60]. International collaborations like the Pediatric Normal Tissue Effects in the Clinic (PENTEC), are systematically analyzing the association between RT doses and volumes and organ toxicities by reviewing published reports of late toxicities following RT in children. However, a large number of reports lack detailed RT doses and organ dose-volume correlations for these reported toxicities. Another approach, as used by the CCSS, is to perform retrospective dosimetry using patient age and sex-matched phantoms to recreate multiorgan dosimetry from past treatments for correlation with late toxicities [61]. A similar approach using patientmatched 3D University of Florida/National Cancer Institute (UF/NCI) phantoms is currently being completed by the NWTS Late Effects Study [60]. A better understanding of the RT dose thresholds for these toxicities will help promote the adoption of interventions for their prevention and mitigation. The revision of previous RT dose thresholds (>20 Gy) for breast cancer surveillance to 12 Gy following reports by the NWTS is an important example of the critical value of such studies [62].

There are many preclinical and clinical reports that describe novel biomarkers that could detect RT injury in various organs more accurately and earlier in the time course after treatment. These biomarkers could greatly improve our understanding of risks of RT and refine surveillance guidelines for high-risk survivors to mitigate late toxicity [63, 64]. Another area of importance that deserves further study is the assessment of risk for late toxicities based on individualized genetic susceptibility to cancer treatment. Currently, while there are no established genetic biomarkers for RT induced toxicities, there are few reports of large-scale genome wide association studies (GWAS) that have identified several single nucleotide polymorphisms (SNPs), linked to breast cancer after RT exposure, cardiovascular toxicity and ovarian failure after cancer therapy [65–67]. The identification of predictive genetic biomarkers that may interact with RT or chemotherapy and increase the likelihood of these toxicities may permit individualized treatment and surveillance guidelines to minimize these risks and maximize long-term quality of life. Currently, the NIH is providing funding opportunities to advance understanding of mechanistic interactions and biologic consequences of RT prioritizing a comprehensive study of patient (genomic and epigenomics), tumor and treatment (chemotherapy, RT, dosimetry) factors, together with longitudinal multiomics (pre and post-therapy) to improve our understanding of the effects of RT on normal tissues (RFA-CA-21-040). Such novel studies could lead to the discovery of new biomarkers and novel therapeutics that could mitigate RT induced complications and improve tumor control rates in children with cancer.

Despite all these advances, there are significant challenges facing health care providers in their efforts to improve the long-term health and quality of life of childhood cancer survivors. The Academy of Medicine (AOM) recommends that cancer survivors be provided survivorship care plans (SCPs) that include treatment summaries and follow-up plans [68]. The '*Passport for Care®'* (PFC) program is a free interactive internet resource for global use that addresses the need to provide childhood cancer survivors and primary care physicians with accurate and individualized health care information based on patients' age, sex, diagnosis, chemotherapy, RT, surgery, clinical history and other related data. The PFC program provides recommendations derived from the long-term COG follow-up guidelines [69]. However, SCPs have not been shown to improve patient reported outcomes due to notable barriers to routine implementation relating to health care providers and survivors such as lack of family and social support for survivors especially among minorities, lack of transition of care, lack of interest and knowledge among primary care providers, knowledge gap among survivors, lack of financial support and psychologic issues including addictions among survivors, among others [70–73]. All of these issues need to be addressed by the global medical community, and new health care models with improved collaboration, better coordination and more communication among survivors and their clinicians will be required to translate the benefits of many of these innovations in late effects research to individual childhood cancer survivors [68, 74].
