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Pediatric Normal Tissue Effects in the Clinic (PENTEC) is an international multidisciplinary effort that aims to summarize normal-tissue toxicity risks based on published dose-volume data from studies of children and adolescents treated with radiation therapy (RT) for cancer. With recognition that children are uniquely vulnerable to treatment-related toxic effects, our mission and challenge was to assemble our group of physicians (radiation and pediatric oncologists, subspecialists), physicists with clinical and modeling expertise, epidemiologists, and other scientists to develop evidence-based radiation dosimetric guidelines, as affected by developmental status and other factors (eg, other cancer therapies and host factors). These quantitative toxicity risk estimates could serve to inform RT planning and thereby improve outcomes. Tandem goals included the description of relevant medical physics issues specific to pediatric RT and the proposal of dose-volume outcome reporting standards to inform future studies. We created 19 organ-specific task forces and methodology to unravel the wealth of data from heterogeneous published studies. This report provides a high-level summary of PENTEC's genesis, methods, key findings, and associated concepts that affected our work and an explanation of how our findings may be interpreted and applied in the clinic. We acknowledge our predecessors in these efforts, and we pay homage to the children whose lives informed us and to future generations who we hope will benefit from this additional step in our path forward. [ABSTRACT FROM AUTHOR]

Relapsed and refractory Hodgkin lymphoma (HL) challenges clinicians to devise treatment strategies that are effective and safe. This problem is particularly prominent in an era when de-escalation trials are designed to minimize therapeutic toxicities in both early- and advanced-stage disease. Radiation therapy is the single most effective treatment modality for HL, and its integration into salvage regimens, or its independent use in select patients, must be understood to maximize our success in treating these patients. The complexity of treating relapsed or refractory HL derives from the spectrum of primary treatment approaches currently in use that creates heterogeneity in both treatment exposure and the potential toxicities of salvage therapy. Patients can have relapsed or refractory disease after limited or aggressive primary therapy (with or without radiation therapy), at early or delayed time points, with limited or extensive disease volumes, and with varying degrees of residual morbidity from primary therapy. Their response to salvage systemic therapy can be partial or complete, and the use of consolidative stem cell transplantation is variably applied. New biologics and immunotherapeutic approaches have broadened but also complicated salvage treatment approaches. Through all of this, radiation therapy remains an integral component of treatment for many patients, but it must be used effectively and judiciously. The purpose of this review is to describe the different treatment scenarios and provide guidance for radiation dose, volume, and timing in patients with relapsed or refractory HL. [ABSTRACT FROM AUTHOR]

The article discusses the side effects of therapeutic interventions on children who survived from cancer. It states that negative impact of brain radiotherapy (RT) on brain tumor patients might result in degrading the quality of life (QoL). Proton therapy (PT) has been used to treat many cancer child patients with an aim to lower the side effects. It talks about the Children's Oncology Group (COG) in U.S. that has proved to be successful in clinical trials for brain tumors in children.

Purpose: Subsequent malignant neoplasms (SMNs) are a dominant cause of morbidity and mortality in children treated for Hodgkin''s disease (HD). We evaluated select demographic and therapeutic factors associated with SMNs, specifically gender and radiation dose. Methods and Materials: A total of 930 children treated for HD at five institutions between 1960 and 1990 were studied. Mean age at diagnosis was 13.6 years, and mean follow-up was 16.8 years (maximum, 39.4 years). Treatment included radiation alone (43%), chemotherapy alone (9%), or both (48%). Results: We found that SMNs occurred in 102 (11%) patients, with a 25-year actuarial rate of 19%. With 15,154 patient years of follow-up, only 7.18 cancers were expected (standardized incidence ratio [SIR] = 14.2; absolute excess risk [AER] = 63 cases/10,000 years). The SIR for female subjects, 19.93, was significantly greater than for males, 8.41 (p < 0.0001). After excluding breast cancer, the SIR for female patients was 15.4, still significantly greater than for male patients (p = 0.0012). Increasing radiation dose was associated with an increasing SIR (p = 0.0085). On univariate analysis, an increased risk was associated with female gender, increasing radiation dose, and age at treatment (12–16 years). Using logistic regression, mantle radiation dose increased risk, and this was 2.5-fold for female patients treated with more than 35 Gy primarily because of breast cancer. Conclusions: Survivors of childhood HD are at risk for SMNs, and this risk is greater for female individuals even after accounting for breast cancer. Although SMNs occur in the absence of radiation therapy, the risk increases with RT dose. [Copyright &y& Elsevier]

The article focuses on treating patients with Hodgkin lymphoma (HL). A study showed that clinically significant morbidities result from modern treatment of HL. The article notes that the impact of cardiovascular disease (CVD) in HL survivors requires periodic definition due to changes in HL therapy that are causative for CVD. Those with higher risk of hospitalisation were survivors of HL who are treated with both anthracycline chemotherapy and radiation therapy.

Pediatric Normal Tissue Effects in the Clinic (PENTEC) seeks to refine quantitative radiation dose-volume relationships for normal-tissue complication probabilities (NTCPs) in survivors of pediatric cancer. This article summarizes the evolution of PENTEC and compares it with similar adult-focused efforts (eg, Quantitative Analysis of Normal Tissue Effects in the Clinic [QUANTEC] and Hypofractionated Treatment Effects in the Clinic [HyTEC]) with respect to content, oversight, support, scope, and methodology of literature review. It then summarizes key organ-specific findings from PENTEC in an attempt to compare NTCP estimates in children versus adults. In brief, select normal-tissue risks within developing organs and tissues (eg, maldevelopment of musculoskeletal tissue, teeth, breasts, and reproductive organs) are primarily relevant only in children. For some organs and tissues, children appear to have similar (eg, brain for necrosis, optic apparatus, parotid gland, liver), greater (eg, brain for neurocognition, cerebrovascular, breast for lactation), less (ovary), or perhaps slightly less (eg, lung) risks of toxicity versus adults. Similarly, even within the broad pediatric age range (including adolescence), for some endpoints, younger children have greater (eg, hearing and brain for neurocognition) or lesser (eg, ovary, thyroid) risks of radiation-associated toxicities. NTCP comparisons in adults versus children are often confounded by marked differences in treatment paradigms that expose normal tissues to radiation (ie, cancer types, prescribed radiation therapy dose and fields, and chemotherapy agents used). To add to the complexity, it is unclear if age is best analyzed as a continuous variable versus with age groupings (eg, infants, young children, adolescents, young adults, middle-aged adults, older adults). Further work is needed to better understand the complex manner in which age and developmental status affect risk. [ABSTRACT FROM AUTHOR]

Radiation myelitis (RM) is a rare complication of radiation therapy (RT). The Pediatric Normal Tissue Effects in the Clinic spinal cord task force aimed to identify RT dose effects and assess risk factors for RM in children. Through systematic review, we analyzed RT dose, fraction size, latency between completion of RT and toxicity, chemotherapy use, age when irradiated, and sex. We conducted literature searches of peer-reviewed manuscripts published from 1964 to June 2017 evaluating RM among children. Normality of variables was assessed with Kolmogorov-Smirnov or Shapiro-Wilk tests. Spearman's rank correlation coefficients were used to test correlations between RT dose/fraction size and latency between RT and development of toxicity. Of 1329 identified and screened reports, 144 reports were fully reviewed and determined to have adequate data for analysis; 16 of these reports had a total of 33 cases of RM with a median age of 13 years (range, 0.2-18) at the time of RT. The most common primary tumor histologies were rhabdomyosarcoma (n = 9), medulloblastoma (n = 5), and Hodgkin lymphoma (n = 2); the most common chemotherapy agents given were vincristine (n = 15), intrathecal methotrexate (n = 12), and intrathecal cytarabine (n = 10). The median RT dose and fraction size were 40 Gy (range, 24-57.4 Gy) and 1.8 Gy (range, 1.3-2.6 Gy), respectively. RT dose resulting in RM in patients who also received chemotherapy was lower than in those not receiving chemotherapy (mean 39.6 vs 49.7 Gy; P =.04). There was no association of age with RT dose. The median latency period was 7 months (range, 1-29). Higher RT dose was correlated with longer latency periods (P =.03) to RM whereas sex, age, fraction size, and chemotherapy use were not. Two of 17 patients with adequate follow-up recovered from RM; unfortunately, it was fatal in 6 of 15 evaluable patients. Complication probability modeling was not possible because of the rarity of events. This report demonstrates a relatively short latency from RT (with or without chemotherapy) to RM and a wide range of doses (including fraction sizes) associated with RM. No apparent association with age at the time of RT could be discerned. Chemotherapy appears to reduce spinal cord tolerance. Recovery from RM is rare, and it is often fatal. [ABSTRACT FROM AUTHOR]

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium has made significant contributions to understanding and mitigating the adverse effects of childhood cancer therapy. This review addresses the role of diagnostic imaging in detecting, screening, and comprehending radiation therapy–related late effects in children, drawing insights from individual organ-specific PENTEC reports. We further explore how the development of imaging biomarkers for key organ systems, alongside technical advancements and translational imaging approaches, may enhance the systematic application of imaging evaluations in childhood cancer survivors. Moreover, the review critically examines knowledge gaps and identifies technical and practical limitations of existing imaging modalities in the pediatric population. Addressing these challenges may expand access to, minimize the risk of, and optimize the real-world application of, new imaging techniques. The PENTEC team envisions this document as a roadmap for the future development of imaging strategies in childhood cancer survivors, with the overarching goal of improving long-term health outcomes and quality of life for this vulnerable population. [ABSTRACT FROM AUTHOR]

The major aim of Pediatric Normal Tissue Effects in the Clinic (PENTEC) was to synthesize quantitative published dose/-volume/toxicity data in pediatric radiation therapy. Such systematic reviews are often challenging because of the lack of standardization and difficulty of reporting outcomes, clinical factors, and treatment details in journal articles. This has clinical consequences: optimization of treatment plans must balance between the risks of toxicity and local failure; counseling patients and their parents requires knowledge of the excess risks encountered after a specific treatment. Studies addressing outcomes after pediatric radiation therapy are particularly challenging because: (a) survivors may live for decades after treatment, and the latency time to toxicity can be very long; (b) children's maturation can be affected by radiation, depending on the developmental status of the organs involved at time of treatment; and (c) treatment regimens frequently involve chemotherapies, possibly modifying and adding to the toxicity of radiation. Here we discuss: basic reporting strategies to account for the actuarial nature of the complications; the reporting of modeling of abnormal development; and the need for standardized, comprehensively reported data sets and multivariate models (ie, accounting for the simultaneous effects of radiation dose, age, developmental status at time of treatment, and chemotherapy dose). We encourage the use of tools that facilitate comprehensive reporting, for example, electronic supplements for journal articles. Finally, we stress the need for clinicians to be able to trust artificial intelligence models of outcome of radiation therapy, which requires transparency, rigor, reproducibility, and comprehensive reporting. Adopting the reporting methods discussed here and in the individual PENTEC articles will increase the clinical and scientific usefulness of individual reports and associated pooled analyses. [ABSTRACT FROM AUTHOR]

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD2 2 ; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD2 2 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P =.46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD2 2 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation. [ABSTRACT FROM AUTHOR]

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) hearing loss (HL) task force reviewed investigations on cochlear radiation dose-response relationships and risk factors for developing HL. Evidence-based dose-response data are quantified to guide treatment planning. A systematic review of the literature was performed to correlate HL with cochlear dosimetry. HL was considered present if a threshold exceeded 20 dB at any frequency. Radiation dose, ototoxic chemotherapy exposure, hearing profile including frequency spectra, interval to HL, and age at radiation therapy (RT) were analyzed. Literature was systematically reviewed from 1970 to 2021. This resulted in 739 abstracts; 19 met inclusion for meta-analysis, and 4 included data amenable to statistical modeling. These 4 studies included 457 cochleas at risk in patients treated with RT without chemotherapy, and 398 cochlea treated with chemotherapy. The incidence and severity of cochlear HL from RT exposure alone is related to dose and age. Risk of HL was <5% in cochlea receiving a mean dose ≤35 Gy but increased to 30% at 50 Gy. HL risk ranged from 25% to 40% in children under the age of 5 years at diagnosis, declining to 10% in older children for any radiation dose. Probability of similar severe HL occurred at doses 18.3 Gy higher for children <3 versus >3 years of age. High-frequency HL was most common, with average onset occurring 3.6 years (range, 0.4-13.2 years) after RT. Exposure to platinum-based chemotherapies added to the rates of HL at a given cochlear dose level, with 300 mg/m2 shifting the dose response by 7 Gy. In children treated with RT alone, risk of HL was low for cochlear dose <35 Gy and rose when dose exceeded 35 Gy without clear RT dose dependence. High-frequency HL was most prevalent, but all frequencies were affected. Children younger than 5 years were at highest risk of developing HL, although independent effects of dose and age were not fully elucidated. Future reports with more granular data are needed to better delineate time to onset of HL and the effects of chemoradiotherapy. [ABSTRACT FROM AUTHOR]

The development of normal tissue radiation dose-response models for children with cancer has been challenged by many factors, including small sample sizes; the long length of follow-up needed to observe some toxicities; the continuing occurrence of events beyond the time of assessment; the often complex relationship between age at treatment, normal tissue developmental dynamics, and age at assessment; and the need to use retrospective dosimetry. Meta-analyses of published pediatric outcome studies face additional obstacles of incomplete reporting of critical dosimetric, clinical, and statistical information. This report describes general methods used to address some of the pediatric modeling issues. It highlights previous single- and multi-institutional pediatric dose-response studies and summarizes how each PENTEC taskforce addressed the challenges and limitations of the reviewed publications in constructing, when possible, organ-specific dose-effect models. [ABSTRACT FROM AUTHOR]

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue–related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon—constituting approximately 1% of new incident cancers in the United States—and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography–based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC. [ABSTRACT FROM AUTHOR]

A PENTEC (Pediatric Normal Tissue Effects in the Clinic) review was performed to estimate the dose-volume effects of radiation therapy on spine deformities and growth impairment for patients who underwent radiation therapy as children. A systematic literature search was performed to identify published data for spine deformities and growth stunting. Data were extracted from 12 reports of children irradiated to the spine (N = 603 patients). The extracted data were analyzed to find associations between complication risks and the radiation dose (conventional fractionation throughout) as impacted by exposed volumes and age using the mixed-effects logistic regression model. When appropriate, corrections were made for radiation modality, namely orthovoltage beams. In the regression analysis, the association between vertebral dose and scoliosis rate was highly significant (P <.001). Additionally, young age at time of radiation was highly predictive of adverse outcomes. Clinically significant scoliosis can occur with doses ≥15 Gy to vertebrae during infancy (<2 years of age). For children irradiated at 2 to 6 years of age, overall scoliosis rates of any grade were >30% with doses >20 Gy; grade 2 or higher scoliosis was correlated with doses ≥30 Gy. Children >6 years of age remain at risk for scoliosis with doses >30 Gy; however, most cases will be mild. There are limited data regarding the effect of dose gradients across the spine on degree of scoliosis. The risk of clinically meaningful height loss was minimal when irradiating small volumes of the spine up to 20 Gy (eg, flank irradiation), except in infants who are more vulnerable to lower doses. Growth stunting was more frequent when larger segments of the spine (eg, the entire spine or craniospinal irradiation) were irradiated before puberty to doses >20 Gy. The effect was modest when patients were irradiated after puberty to doses >20 Gy. To reduce the risk of kyphoscoliosis and growth impairment, the dose to the spine should be kept to <20 Gy for children <6 years of age and to <10 to 15 Gy in infants. The number of vertebral bodies irradiated and dose gradients across the spine should also be limited when possible. [ABSTRACT FROM AUTHOR]

A pediatric normal tissue effects in the clinic (PENTEC) comprehensive review of patients with childhood cancer who received radiation therapy (RT) to the liver was performed to develop models that may inform RT dose constraints for the liver and improve risk forecasting of toxicities. A systematic literature search was performed to identify published data on hepatic toxicities in children. Treatment and outcome data were extracted and used to generate normal tissue complication probability (NTCP) models. Complications from both whole and partial liver irradiation were considered. For whole liver irradiation, total body irradiation and non–total body irradiation treatments were considered, but it was assumed that the entire liver received the prescribed dose. For partial liver irradiation, only Wilms tumor flank field RT could be analyzed. However, a prescribed dose assumption could not be applied, and there was a paucity of analyzable liver dosimetry data. To associate the dose-volume exposures with the partial volume complication data from flank irradiation, liver dose-volume metrics were reconstructed for Wilms tumor flank RT using age-specific computational phantoms as a function of field laterality and superior extent of the field. The literature search identified 2103 investigations pertaining to hepatic sinusoidal obstructive syndrome (SOS) and liver failure in pediatric patients. All abstracts were screened, and 241 articles were reviewed in full by the study team. A model was developed to calculate the risk of developing SOS after whole liver RT. RT dose (P =.006) and receipt of nonalkylating chemotherapy (P =.01) were significant. Age <20 years at time of RT was borderline significant (P =.058). The model predicted a 2% risk of SOS with zero RT dose, 6.1% following 10 Gy, and 14.5% following 20 Gy to the whole liver (modeled as the linear-quadratic equivalent dose in 2-Gy fractions [α/β = 3 Gy]). Patients with Wilms tumor treated with right flank RT had a higher observed rate of SOS than patients receiving left flank RT, but data were insufficient to generate an NTCP model for partial liver irradiation. From the phantom-based dose reconstructions, mean liver dose was estimated to be 2.16 ± 1.15 Gy and 6.54 ± 2.50 Gy for left and right flank RT, respectively, using T10-T11 as the superior field border and a prescription dose of 10.8 Gy (based on dose reconstruction). Data were sparse regarding rates of late liver injury after RT, which suggests low rates of severe toxicity after treatment for common pediatric malignancies. This pediatric normal tissue effects in the clinic (PENTEC) review provides an NTCP model to estimate the risk of hepatic SOS as a function of RT dose following whole liver RT and quantifies the range of mean liver doses from typical Wilms tumor flank irradiation fields. Patients treated with right flank RT had higher rates of SOS than patients treated with left flank RT, but data were insufficient to develop a model for partial liver irradiation. Risk of SOS was estimated to be approximately ≤6% in pediatric patients receiving whole liver doses of <10 Gy. [ABSTRACT FROM AUTHOR]

Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P =.0004). The model-predicted odds ratio for IPS was 24.3 Gy–1 (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed. [ABSTRACT FROM AUTHOR]

A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors. A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated. The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P <.0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs. This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Few reports describe the risks of late ocular toxicities after radiation therapy (RT) for childhood cancers despite their effect on quality of life. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) ocular task force aims to quantify the radiation dose dependence of select late ocular adverse effects. Here, we report results concerning retinopathy, optic neuropathy, and cataract in childhood cancer survivors who received cranial RT. A systematic literature search was performed using the PubMed, MEDLINE, and Cochrane Library databases for peer-reviewed studies published from 1980 to 2021 related to childhood cancer, RT, and ocular endpoints including dry eye, keratitis/corneal injury, conjunctival injury, cataract, retinopathy, and optic neuropathy. This initial search yielded abstracts for 2947 references, 269 of which were selected as potentially having useful outcomes and RT data. Data permitting, treatment and outcome data were used to generate normal tissue complication probability models. We identified sufficient RT data to generate normal tissue complication probability models for 3 endpoints: retinopathy, optic neuropathy, and cataract formation. Based on limited data, the model for development of retinopathy suggests 5% and 50% risk of toxicity at 42 and 62 Gy, respectively. The model for development of optic neuropathy suggests 5% and 50% risk of toxicity at 57 and 64 Gy, respectively. More extensive data were available to evaluate the risk of cataract, separated into self-reported versus ophthalmologist-diagnosed cataract. The models suggest 5% and 50% risk of self-reported cataract at 12 and >40 Gy, respectively, and 50% risk of ophthalmologist-diagnosed cataract at 9 Gy (>5% long-term risk at 0 Gy in patients treated with chemotherapy only). Radiation dose effects in the eye are inadequately studied in the pediatric population. Based on limited published data, this PENTEC comprehensive review establishes relationships between RT dose and subsequent risks of retinopathy, optic neuropathy, and cataract formation. [ABSTRACT FROM AUTHOR]

The PENTEC (Pediatric Normal Tissue Effects in the Clinic) task force aimed to quantify effects of radiation therapy (RT) dose to the female reproductive organs after treatment for childhood cancer. Relevant studies published 1970 to 2017 were identified systematically through PubMed, Medline, and Cochrane databases with additional articles before 2021 identified by the group. Two large studies reported sufficient data to allow modeling of acute ovarian failure (AOF; loss of function ≤5 year from diagnosis) and premature ovarian insufficiency (POI; loss of function at attained age <40 years) based on maximum dose to least affected ovary. Although normal tissue complication probability modeling was not feasible for the uterus due to limited data, the relationship between ultrasound-measured uterine volume and estimated amount of RT was plotted. Limited data regarding vaginal toxicity were available. The risk of AOF increases with RT dose to least affected ovary, alkylating agent cumulative dose (cyclophosphamide equivalent dose [CED] in g/m2), age at RT, and stem cell transplantation: Two Gy to the least affected ovary resulted in AOF risk of 1% to 5% (CED = 0, risk increasing with age), 4% to 7% (CED = 10 g/m2, risk increasing with age), and 6% to 13% (CED = 30 g/m2, risk increasing with age). For patients aged 1 and 20 years at time of RT, AOF risk was ≥50% at doses of 24 Gy and 20 Gy with no alkylating chemotherapy, 22.5 Gy and 17 Gy with intermediate alkylator dose (10 g/m2), and 17 Gy and 13 Gy with high alkylator dose (30 g/m2). Risk of POI increases with survivor (attained) age (rather than age at time of RT), radiation dose to least affected ovary, and alkylator dose. Data review suggested that higher radiation doses to the uterus are associated with uterine toxicity, with uterine size considerably restricted after 12 Gy. Vaginal radiation in children is associated with high toxicity risk, although dose-volume data are not available for quantification. Risk of AOF increases with age at RT, CED exposure, and RT dose; risk of POI likewise increases with RT dose, CED exposure, and survivor age. Both AOF and POI are expected to affect fertility and estrogen production. Data suggest that RT uterine dose >12 Gy may be associated with uterine size restriction. Adult literature suggests that maintaining vaginal dose <5 Gy may limit toxicity. Treatment of life-threatening malignancy remains a priority over reproductive preservation; however, when possible, radiation and surgical techniques should be considered to minimize dose to least affected ovary, uterus, and vagina. Survivors should receive endocrine and gynecologic support; those desiring pregnancy should be counseled early to maximize reproductive options. [ABSTRACT FROM AUTHOR]

The male reproductive task force of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative performed a comprehensive review that included a meta-analysis of publications reporting radiation dose-volume effects for risk of impaired fertility and hormonal function after radiation therapy for pediatric malignancies. The PENTEC task force conducted a comprehensive literature search to identify published data evaluating the effect of testicular radiation dose on reproductive complications in male childhood cancer survivors. Thirty-one studies were analyzed, of which 4 had testicular dose data to generate descriptive scatter plots. Two cohorts were identified. Cohort 1 consisted of pediatric and young adult patients with cancer who received scatter radiation therapy to the testes. Cohort 2 consisted of pediatric and young adult patients with cancer who received direct testicular radiation therapy as part of their cancer therapy. Descriptive scatter plots were used to delineate the relationship between the effect of mean testicular dose on sperm count reduction, testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels. Descriptive scatter plots demonstrated a 44% to 80% risk of oligospermia when the mean testicular dose was <1 Gy, but this was recovered by >12 months in 75% to 100% of patients. At doses >1 Gy, the rate of oligospermia increased to >90% at 12 months. Testosterone levels were generally not affected when the mean testicular dose was <0.2 Gy but were abnormal in up to 25% of patients receiving between 0.2 and 12 Gy. Doses between 12 and 19 Gy may be associated with abnormal testosterone in 40% of patients, whereas doses >20 Gy to the testes were associated with a steep increase in abnormal testosterone in at least 68% of patients. FSH levels were unaffected by a mean testicular dose <0.2 Gy, whereas at doses >0.5 Gy, the risk was between 40% and 100%. LH levels were affected at doses >0.5 Gy in 33% to 75% of patients between 10 and 24 months after radiation. Although dose modeling could not be performed in cohort 2, the risk of reproductive toxicities was escalated with doses >10 Gy. This PENTEC comprehensive review demonstrates important relationships between scatter or direct radiation dose on male reproductive endpoints including semen analysis and levels of FSH, LH, and testosterone. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) is an essential component in the treatment of many pediatric malignancies. Thoracic RT may expose the heart to radiation dose and thereby increase the risk of late cardiac disease. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on late cardiac disease in survivors of childhood cancer treated with RT. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We identified 1496 articles; 4 were included for dose-response modeling between mean cardiac radiation dose and risk of late coronary artery disease, heart failure (HF), valvular disease, and any cardiac disease. For each 10-Gy increase in corrected mean cardiac radiation dose in 1.8- to 2.0-Gy fractions, we estimated a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25) for coronary artery disease, of 1.87 (95% CI, 1.70-2.06) for HF, of 1.87 (95% CI, 1.78-1.96) for valvular disease, and of 1.88 (95% CI, 1.75-2.03) for any cardiac disease. From the same model, for each 100-mg/m2 increase in cumulative anthracycline dose, the hazard ratio for the development of HF was 1.93 (95% CI, 1.58-2.36), equivalent to an increase in mean heart dose of approximately 10.5 Gy. Other nontreatment factors were inconsistently reported in the analyzed articles. Radiation dose to the heart increases the risk of late cardiac disease, but survivors of childhood cancer who receive a mean dose <10 Gy at standard fractionation are at low absolute risk (<∼2% approximately 30 years after exposure) of late cardiac disease in the absence of anthracycline exposure. Minimizing cardiac radiation dose is especially relevant in children receiving anthracyclines. When cardiac sparing is not possible, we recommend prioritizing target coverage. It is likely that individual cardiac substructure doses will be a better predictor of specific cardiac diseases than mean dose, and we urge the pediatric oncology community to further study these relationships. [ABSTRACT FROM AUTHOR]

Kidney injury is a known late and potentially devastating complication of abdominal radiation therapy (RT) in pediatric patients. A comprehensive Pediatric Normal Tissue Effects in the Clinic review by the Genitourinary (GU) Task Force aimed to describe RT dose-volume relationships for GU dysfunction, including kidney, bladder, and hypertension, for pediatric malignancies. The effect of chemotherapy was also considered. We conducted a comprehensive PubMed search of peer-reviewed manuscripts published from 1990 to 2017 for investigations on RT-associated GU toxicities in children treated for cancer. We retrieved 3271 articles with 100 fulfilling criteria for full review, 24 with RT dose data and 13 adequate for modeling. Endpoints were heterogenous and grouped according to National Kidney Foundation: grade ≥1, grade ≥2, and grade ≥3. We modeled whole kidney exposure from total body irradiation (TBI) for hematopoietic stem cell transplant and whole abdominal irradiation (WAI) for patients with Wilms tumor. Partial kidney tolerance was modeled from a single publication from 2021 after the comprehensive review revealed no usable partial kidney data. Inadequate data existed for analysis of bladder RT-associated toxicities. The 13 reports with long-term GU outcomes suitable for modeling included 4 on WAI for Wilms tumor, 8 on TBI, and 1 for partial renal RT exposure. These reports evaluated a total of 1191 pediatric patients, including: WAI 86, TBI 666, and 439 partial kidney. The age range at the time of RT was 1 month to 18 years with medians of 2 to 11 years in the various reports. In our whole kidney analysis we were unable to include chemotherapy because of the heterogeneity of regimens and paucity of data. Age-specific toxicity data were also unavailable. Wilms studies occurred from 1968 to 2011 with mean follow-ups 8 to 15 years. TBI studies occurred from 1969 to 2004 with mean follow-ups of 4 months to 16 years. We modeled risk of dysfunction by RT dose and grade of toxicity. Normal tissue complication rates ≥5%, expressed as equivalent doses, 2 Gy/fx for whole kidney exposures occurred at 8.5, 10.2, and 14.5 Gy for National Kidney Foundation grades ≥1, ≥2, and ≥3, respectively. Conventional Wilms WAI of 10.5 Gy in 6 fx had risks of ≥grade 2 toxicity 4% and ≥grade 3 toxicity 1%. For fractionated 12 Gy TBI, those risks were 8% and <3%, respectively. Data did not support whole kidney modeling with chemotherapy. Partial kidney modeling from 439 survivors who received RT (median age, 7.3 years) demonstrated 5 or 10 Gy to 100% kidney gave a <5% risk of grades 3 to 5 toxicity with 1500 mg/m2 carboplatin or no chemo. With 480 mg/m2 cisplatin, a 3% risk of ≥grade 3 toxicity occurred without RT and a 5% risk when 26% kidney received ≥10 Gy. With 63 g/m2 of ifosfamide, a 5% risk of ≥grade 3 toxicity occurred with no RT, and a 10% toxicity risk occurred when 42% kidney received ≥10 Gy. In patients with Wilms tumor, the risk of toxicity from 10.5 Gy of WAI is low. For 12 Gy fractionated TBI with various mixtures of chemotherapy, the risk of severe toxicity is low, but low-grade toxicity is not uncommon. Partial kidney data are limited and toxicity is associated heavily with the use of nephrotoxic chemotherapeutic agents. Our efforts demonstrate the need for improved data gathering, systematic follow-up, and reporting in future clinical studies. Current radiation dose used for Wilms tumor and TBI appear to be safe; however, efforts in effective kidney-sparing TBI and WAI regimens may reduce the risks of renal injury without compromising cure. [ABSTRACT FROM AUTHOR]

Children who receive cranial radiation therapy (RT) as a component of treatment for malignancy are often at risk of long-term central endocrine toxicity secondary to radiation to the hypothalamic-pituitary axis (HPA). A comprehensive analysis was performed of central endocrine late effects in survivors of childhood cancer treated with RT as part of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium. A systematic review of the risk of RT-related central endocrine effects was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 4629 publications were identified, of which 16 met criteria for inclusion in dose modeling analysis, with a total of 570 patients in 19 cohorts. Eighteen cohorts reported outcomes for growth hormone deficiency (GHD), 7 reported outcomes for central hypothyroidism (HT), and 6 reported outcomes for adrenocorticotropic hormone (ACTH) deficiency. Normal tissue complication probability modeling for GHD (18 cohorts, 545 patients) yielded D 50 = 24.9 Gy (95% CI, 20.9-28.0) and γ 50 = 0.5 (95% CI, 0.27-0.78). The normal tissue complication probability model fit for whole brain irradiation in children with a median age of >5 years indicated a 20% risk of GHD for patients who receive a mean dose of 21 Gy in 2-Gy fractions to the HPA. For HT, among 7 cohorts (250 patients), D 50 = 39 Gy (95% CI, 34.1-53.2) and γ 50 = 0.81 (95% CI, 0.46-1.35), with a 20% risk of HT in children who receive a mean dose of 22 Gy in 2-Gy fractions to the HPA. For ACTH deficiency (6 cohorts, 230 patients), D 50 = 61 Gy (95% CI, 44.7-119.4) and γ 50 = 0.76 (95% CI, 0.5-1.19); there is a 20% risk of ACTH deficiency in children who receive a mean dose of 34 Gy in 2-Gy fractions to the HPA. RT dose to the HPA increases the risk of central endocrine toxicity, including GHD, HT, and ACTH deficiency. In some clinical situations, these toxicities may be difficult to avoid, and counseling of patients and families with respect to anticipated outcomes is important. [ABSTRACT FROM AUTHOR]

Radiation-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial irradiation. A literature search was performed for studies reporting pediatric radiation therapy (RT) associated cerebral vasculopathy. When available, we used individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. The search identified 766 abstracts, 5 of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack, stroke, moyamoya , or arteriopathy. For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9% to 1.3%, 1.8% to 2.7%, and 2.8% to 4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.2%-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1% to 4.2%, 4.5% to 8.6%, and 6.7% to 13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.5%-1.0%). Risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population. [ABSTRACT FROM AUTHOR]

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) pulmonary task force reviewed dosimetric and clinical factors associated with radiation therapy (RT)–associated pulmonary toxicity in children. Comprehensive search of PubMed (1965-2020) was conducted to assess available evidence and predictive models of RT-induced lung injury in pediatric cancer patients (<21 years old). Lung dose for radiation pneumonitis (RP) was obtained from dose-volume histogram (DVH) data. RP grade was obtained from standard criteria. Clinical pulmonary outcomes were evaluated using pulmonary function tests (PFTs), clinical assessment, and questionnaires. More than 2,400 abstracts were identified; 460 articles had detailed treatment and toxicity data; and 11 articles with both detailed DVH and toxicity data were formally reviewed. Pooled cohorts treated during 1999 to 2016 included 277 and 507 patients age 0.04 to 22.7 years who were evaluable for acute and late RP analysis, respectively. After partial lung RT, there were 0.4% acute and 2.8% late grade 2, 0.4% acute and 0.8% late grade 3, and no grade 4 to 5 RP. RP risk after partial thoracic RT with mean lung dose (MLD) <14 Gy and total lung V 20Gy <30% is low. Clinical and self-reported pulmonary outcomes data included 8,628 patients treated during 1970 to 2013, age 0 to 21.9 years. At a median 2.9- to 21.9-year follow-up, patients were often asymptomatic; abnormal PFTs were common and severity correlated with lung dose. At ≥10-year follow-up, multi-institutional studies suggested associations between total or ipsilateral lung doses >10 Gy and pulmonary complications and deaths. After whole lung irradiation (WLI), pulmonary toxicity is higher; no dose response relationship was identified. Bleomycin and other chemotherapeutics at current dose regimens do not contribute substantially to adverse pulmonary outcomes after partial lung irradiation but increase risk with WLI. After partial lung RT, acute pulmonary toxicity is uncommon; grade 2 to 3 RP incidences are <1%. Late toxicities, including subclinical/asymptomatic impaired pulmonary function, are more common (<4%). Incidence and severity appear to increase over time. Upon review of available literature, there appears to be low risk of pulmonary complications in children with MLD < 14 Gy and V 20Gy <30% using standard fractionated RT to partial lung volumes. A lack of robust data limit guidance on lung dose/volume constraints, highlighting the need for additional work to define factors associated with RT-induced lung injury. [ABSTRACT FROM AUTHOR]

Breast hypoplasia and impaired lactation are poorly studied sequelae of chest radiation therapy (RT) in children. The Pediatric Normal Tissue Effects in the Clinic female breast task force aimed to quantitate the radiation dose-volume effects on these endpoints. A literature search was conducted of peer-reviewed manuscripts evaluating breast hypoplasia and lactation after chest RT in children, yielding 789 abstracts. Only 2 studies on children irradiated at <4 years of age for angioma of the breast provided dosimetric data correlated with breast hypoplasia. For patients who received brachytherapy, the dose was converted to external beam RT in equivalent 2 Gy fractions (D EBRT), although the limitations of this type of mathematical conversion need to be recognized. We calculated relative risks (RR) and 95% confidence intervals (95% CIs) based on these data. Only 1 study was relevant to the lactation endpoint, in which patients were given RT for Hodgkin lymphoma at age 14 to 40 years. The 3 studies involved 206 patients in total. In patients <4 years old at the time of RT, the prevalence of patient-perceived breast hypoplasia was 38% (RR 2.5; 95% CI, 1.3-4.6) after D EBRT of <0.34 Gy, 61% (RR 4.0; 95% CI, 2.1-7.4) after D EBRT 0.34-0.97 Gy, and 97% (RR 6.3; 95% CI, 3.6-10.8) after D EBRT ≥0.97 Gy to the breast anlage. A simple linear regression model (r = 0.72; P <.001) showed that the treated breast was smaller than the untreated breast by 13% at D EBRT = 0.5 Gy, 20% at D EBRT = 1 Gy, 32% at D EBRT = 2 Gy, 51% at D EBRT = 4 Gy, 66% at D EBRT = 6 Gy, 79% at D EBRT = 8 Gy, and 90% at D EBRT = 10 Gy. The risk of unsuccessful breastfeeding was 39% after a median mediastinal dose of 41 Gy, compared with 21% in a sibling control group (P =.04). RT dose of ≥42 Gy was not associated with less breastfeeding success compared with <42 Gy, and data on lower doses were unavailable. Based on extremely limited data, young adults exposed to thoracic RT as children seem to be at significant risk of breast hypoplasia and impaired lactation. Doses as low as 0.3 Gy to immature breasts can cause breast hypoplasia. Additional studies are needed to quantify dose and technique effects with modern RT indications. Prospective collection of clinical outcomes and dosimetric factors would enhance our understanding of RT-induced breast hypoplasia and impaired lactation. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) to the head and neck (H&N) region is critical in the management of various pediatric malignancies; however, it may result in late toxicity. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on salivary dysfunction and dental abnormalities in survivors who received RT to the H&N region as children. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. Of the 2,164 articles identified through a literature search, 40 were included in a qualitative synthesis and 3 were included in a quantitative synthesis. The dose-toxicity data regarding salivary function demonstrate that a mean parotid dose of 35 to 40 Gy is associated with a risk of acute and chronic grade ≥2 xerostomia of approximately 32% and 13% to 32%, respectively, in patients treated with chemo-radiation therapy. This risk increases with parotid dose; however, rates of xerostomia after lower dose exposure have not been reported. Dental developmental abnormalities are common after RT to the oral cavity. Risk factors include higher radiation dose to the developing teeth and younger age at RT. This PENTEC task force considers adoption of salivary gland dose constraints from the adult experience to be a reasonable strategy until more data specific to children become available; thus, we recommend limiting the parotid mean dose to ≤26 Gy. The minimum toxic dose for dental developmental abnormalities is unknown, suggesting that the dose to the teeth should be kept as low as possible particularly in younger patients, with special effort to keep doses <20 Gy in patients <4 years old. [ABSTRACT FROM AUTHOR]

From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative, a systematic review and meta-analysis of publications reporting on radiation dose-volume effects for risk of primary hypothyroidism after radiation therapy for pediatric malignancies was performed. All studies included childhood cancer survivors, diagnosed at age <21 years, whose radiation therapy fields exposed the thyroid gland and who were followed for primary hypothyroidism. Children who received pituitary-hypothalamic or total-body irradiation were excluded. PubMed and the Cochrane Library were searched for studies published from 1970 to 2017. Data on age at treatment, patient sex, radiation dose to neck or thyroid gland, specific endpoints for hypothyroidism that were used in the studies, and reported risks of hypothyroidism were collected. Radiation dose-volume effects were modeled using logistic dose response. Relative excess risk of hypothyroidism as a function of age at treatment and sex was assessed by meta-analysis of reported relative risks (RR) and odds ratios. Fifteen publications (of 1709 identified) were included for systematic review. Eight studies reported data amenable for dose-response analysis. At mean thyroid doses of 10, 20, and 30 Gy, predicted rates of uncompensated (clinical) hypothyroidism were 4%, 7%, and 13%, respectively. Predicted rates of compensated (subclinical) hypothyroidism were 12%, 25%, and 44% after thyroid doses of 10, 20, and 30 Gy, respectively. Female sex (RR = 1.7, P <.0001) and age >15 years at radiation therapy (RR = 1.3, P =.005) were associated with higher risks of hypothyroidism. After a mean thyroid dose of 20 Gy, predicted risks of hypothyroidism were 13% for males <14 years of age, increasing to 29% for females >15 years of age. A radiation dose response for risk of hypothyroidism is evident; a threshold radiation dose associated with no risk is not observed. Thyroid dose exposure should be minimized when feasible. Data on hypothyroidism after radiation therapy should be better reported to facilitate pooled analyses. [ABSTRACT FROM AUTHOR]

The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)–compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial. Pediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject. Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P =.04) and private versus public insurance (P <.001). Both patient (P =.008) and parent (P =.006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P <.001), by age (P <.001), and by S versus NS patients (P <.001). In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P <.001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction. [ABSTRACT FROM AUTHOR]

Purpose: The intrusive thoughts of cancer diagnosis, treatments, re-experiencing, and avoidance associated with post-traumatic stress symptoms (PTSS) can negatively affect Hodgkin lymphoma (HL) survivors. This study investigates the associations between experiences and beliefs and PTSS among adolescent survivors of intermediate-risk HL treated on the Children's Oncology Group (COG) AHOD0031 study. Methods: COG AHOD0031 participants completed self-report surveys at end of therapy concerning post-treatment medical conditions, activity limitations, fatigue, future concerns, exercise, and PTSS. Results: One thousand one hundred ten of 1721 participants in AHOD0031 completed the first survey at a median of 6.7 months post-diagnosis (interquartile range: 5.3–11.5 months), and of these, 736 (66.3%) completed a second survey at a median of 12.4 (10.1–17.6) months following the first. The mean PTSS score (ranging from 0 to 20) was 5.5 (standard deviation [SD] = 5.1) on survey 1 and 4.4 (SD = 4.8) on survey 2. Increased fatigue (odds ratio [OR] = 1.14, p < 0.01), concerns for the future (OR = 1.13, p < 0.01), activity limitations (OR = 1.05, p < 0.01), and relapse history (OR = 2.18, p < 0.05) were associated with higher PTSS scores in the initial survey. Increased fatigue (OR = 1.16, p < 0.01), concerns for the future (OR = 1.14, p < 0.01), activity limitations (OR = 1.05, p < 0.05), and higher PTSS scores on the first survey (OR = 1.19, p < 0.01) were associated with higher PTSS scores in the subsequent survey. Longer time since diagnosis (OR = 0.85, p < 0.05; OR = 0.84, p < 0.05) was associated with lower PTSS scores on both surveys. Conclusions: Based on our findings, future research should examine the onset and trajectory of PTSS among HL survivors, focusing on early recognition and intervention to improve quality of life. [ABSTRACT FROM AUTHOR]

Advances in dose–volume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal Emami paper from 1991 are reviewed. There has been some progress with an increasing number of studies on large patient samples with three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity, and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and variations in the models and predictors analyzed. Clinical limitations to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall treatment time in relation to nonuniform dose distributions. Research priorities for the next 5–10 years are proposed. [Copyright &y& Elsevier]

The literature is reviewed to identify the main clinical and dose–volume predictors for acute and late radiation-induced heart disease. A clear quantitative dose and/or volume dependence for most cardiac toxicity has not yet been shown, primarily because of the scarcity of the data. Several clinical factors, such as age, comorbidities and doxorubicin use, appear to increase the risk of injury. The existing dose-volume data is presented, as well as suggestions for future investigations to better define radiation-induced cardiac injury. [Copyright &y& Elsevier]

Purpose: Survivors of pediatric Hodgkin lymphoma (HL) are recognized to have an increased risk of delayed adverse health outcomes related to radiation therapy (RT). However, the necessary latency required to observe these late effects means that the estimated risks apply to outdated treatments. We sought to compare the normal tissue dose received by children treated for HL and enrolled in the Childhood Cancer Survivor Study (CCSS) (diagnosed 1970-1986) with that of patients treated in recent Children's Oncology Group (COG) trials (enrolled 2002-2012).Methods and Materials: RT planning data were obtained for 50 HL survivors randomly sampled from the CCSS cohort and applied to computed tomography planning data sets to reconstruct the normal tissue dosimetry. For comparison, the normal tissue dosimetry data were obtained for all 191 patients with full computed tomography-based volumetric RT planning on COG protocols AHOD0031 and AHOD0831.Results: For early-stage patients, the mean female breast dose in the COG patients was on average 83.5% lower than that for CCSS patients, with an absolute reduction of 15.5 Gy. For advanced-stage patients, the mean breast dose was decreased on average by 70% (11.6 Gy average absolute dose reduction). The mean heart dose decreased on average by 22.9 Gy (68.6%) and 17.6 Gy (56.8%) for early- and advanced-stage patients, respectively. All dose comparisons for breast, heart, lung, and thyroid were significantly lower for patients in the COG trials than for the CCSS participants. Reductions in the prescribed dose were a major contributor to these dose reductions.Conclusions: These are the first data quantifying the significant reduction in the normal tissue dose using actual, rather than hypothetical, treatment plans for children with HL. These findings provide useful information when counseling families regarding the risks of contemporary RT. [ABSTRACT FROM AUTHOR]

Background: Patients with brain tumors who are treated with radiation frequently have growth hormone deficiency, but other neuroendocrine abnormalities are presumed to be uncommon. Methods: We studied endocrine function in 32 patients (age, 6 to 65 years) 2 to 13 years after they had received cranial radiotherapy for brain tumors. The doses of radiation to the hypothalamic-pituitary region ranged from 3960 to 7020 rad (39.6 to 70.2 Gy). Nine patients also received 1800 to 3960 rad (18.0 to 39.6 Gy) to the craniospinal axis. Serum concentrations of thyroid, gonadal, and pituitary hormones were measured at base line and after stimulation. Results: Nine patients (28 percent) had symptoms of thyroid deficiency, and 20 patients (62 percent) had low serum total or free thyroxine or total triiodothyronine concentrations. Of the 23 patients treated only with cranial radiation, 15 (65 percent) had hypothalamic or pituitary hypothyroidism. Of the nine patients who also received spinal (and thus direct thyroid) radiation, three (33 percent) had evidence of primary thyroid injury. Seven of the 10 postpubertal, premenopausal women (70 percent) had oligomenorrhea, and 5 (50 percent) had low serum estradiol concentrations. Three of the 10 men (30 percent) had low serum testosterone concentrations. Overall, 14 of the 23 postpubertal patients (61 percent) had evidence of hypogonadism. Mild hyperprolactinemia was present in 50 percent of the patients. Responses to stimulation with corticotropin-releasing hormone and corticotropin were normal in all patients except one, who had panhypothalamic dysfunction. However, serum 11-deoxycortisol responses to the administration of metyrapone were low in 11 of the 31 patients (35 percent) tested. Three of the 32 patients (9 percent) had no endocrine abnormalities, 9 (28 percent) had an abnormal result on tests of thyroid, gonadal, prolactin, or adrenal function, 8 (25 percent) had abnormalities in two axes, 8 (25 percent) in three axes, and 4 (12 percent) in all four axes. Conclusions: Cranial radiotherapy in children and adults with brain tumors frequently causes abnormal hypothalamic-pituitary function. The most frequent changes are hypothyroidism and gonadal dysfunction, although subtle abnormalities in adrenal function may also be present. (N Engl J Med 1993;328:87-94.) [ABSTRACT FROM AUTHOR]

For early-stage NLPHL, AV-PC is most frequently utilized by physicians treating children ( I p i <.001), whereas for advanced-stage NLPHL, AV-PC is most frequently utilized by physicians treating both adults and children ( I p i <.001). Physicians treating adults were significantly more likely to incorporate RT into the treatment of NLPHL (94% versus 59% of physicians treating children and 60% of physicians treating both; I p i <.001), particularly for early-stage disease (Table 1). Bold> .001RT is incorporated into the upfront treatment of early-stage NLPHL .001 Never or rarely95 (72%)7 (9%)6 (24%) Sometimes, usually, or always25 (19%)70 (90%)12 (48%)Factors that are considered in the incorporation of RT into the upfront treatment of early-stage NLPHL Age16 (12%)47 (60%)11 (44%)< Keywords: Nodular lymphocyte-predominant Hodgkin lymphoma; global health; lymphoma EN Nodular lymphocyte-predominant Hodgkin lymphoma global health lymphoma 1997 2000 4 08/22/22 20220801 NES 220801 To the Editor Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL) in both children and adults. [Extracted from the article]

Educational achievement and employment outcomes are critical indicators of quality of life in survivors of childhood, adolescent, and young adult (CAYA) cancer. This review is aimed at providing an evidence‐based clinical practice guideline (CPG) with internationally harmonized recommendations for the surveillance of education and employment outcomes in survivors of CAYA cancer diagnosed before the age of 30 years. The CPG was developed by a multidisciplinary panel under the umbrella of the International Late Effects of Childhood Cancer Guideline Harmonization Group. After evaluating concordances and discordances of 4 existing CPGs, the authors performed a systematic literature search through February 2021. They screened articles for eligibility, assessed quality, and extracted and summarized the data from included articles. The authors formulated recommendations based on the evidence and clinical judgment. There were 3930 articles identified, and 83 of them, originating from 17 countries, were included. On a group level, survivors were more likely to have lower educational achievement and more likely to be unemployed than comparisons. Key risk factors for poor outcomes included receiving a primary diagnosis of a central nervous system tumor and experiencing late effects. The authors recommend that health care providers be aware of the risk of educational and employment problems, implement regular surveillance, and refer survivors to specialists if problems are identified. In conclusion, this review presents a harmonized CPG that aims to facilitate evidence‐based care, positively influence education and employment outcomes, and ultimately minimize the burden of disease and treatment‐related late adverse effects for survivors of CAYA cancers. Lay Summary: A multidisciplinary panel has developed guidelines for the surveillance of education and employment outcomes among survivors of childhood, adolescent, and young adult cancer.On the basis of evidence showing that survivors are at risk for lower educational achievement and unemployment, it is recommended that all survivors receive regular screening for educational and employment outcomes. A systematic review of the literature indicates that survivors of childhood, adolescent, and young adult cancer are at risk for lower educational achievement and unemployment. It is recommended that all survivors receive regular screening for educational and employment outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND Despite improved cure rates for bone and soft tissue sarcomas, to the authors' knowledge, no large population-based study to date has evaluated long-term cause-specific mortality in patients diagnosed in the adolescent and young adult (AYA) age range (15 years-39 years). METHODS A total of 28,844 survivors of AYA bone and soft tissue sarcoma, who accrued 113,206 person-years of follow-up, were identified in the population-based Surveillance, Epidemiology, and End Results program. Standardized mortality ratios (SMR) and absolute excess risks (AER) (per 10,000 person-years) were calculated to evaluate associations with histology (chemotherapy-sensitive subtypes: Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma vs all other subtypes), age, and initial therapy. RESULTS All-cause mortality in survivors of AYA sarcoma was found to be significantly increased compared with that of the general population (SMR, 1.76; 95% confidence interval [95% CI], 1.60-1.92 [AER of 19]), and persisted for > 20 years (SMR, 1.39; 95% CI, 1.04-1.82 [AER of 20]). Significant excess mortality was observed for both second malignant neoplasms (SMR, 2.05; 95% CI, 1.71-2.43 [AER of 7]) and noncancer causes (SMR, 1.66; 95% CI, 1.49-1.85 [AER of 19]). Significant excess deaths occurred among patients with chemotherapy-sensitive (SMR, 2.76; 95% CI, 2.20-3.41 [AER of 32]) and nonchemosensitive (SMR, 1.63; 95% CI, 1.47-1.80 [AER of 17]) subtypes. Significantly elevated noncancer mortality in the former group included cardiovascular disease (SMR, 2.33) and infections (SMR, 15.6), whereas significant excess deaths in the latter group included diabetes (SMR, 2.40) and infections (SMR, 2.77). CONCLUSIONS Survivors of AYA bone and soft tissue sarcoma experience significant long-term mortality due to second malignant neoplasms and noncancer causes. Further research is needed to develop preventive and surveillance guidelines in this understudied population to prevent and reduce long-term excess mortality. Cancer 2014;120:2334-2342. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Survivors of childhood, adolescent, and young adult (diagnosed when <25 years of age) cancer are at risk of mental health problems. The aim of this clinical practice guideline is to harmonise international recommendations for mental health surveillance in survivors of childhood, adolescent, and young adult cancer. This guideline was developed by a multidisciplinary panel of experts under the sponsorship of the International Guideline Harmonization Group. We evaluated concordance among existing survivorship clinical practice guidelines and conducted a systematic review following evidence-based methods. Of 7249 studies identified, 76 articles from 12 countries met the inclusion criteria. Recommendations were formulated on the basis of identified evidence in combination with clinical considerations. This international clinical practice guideline strongly recommends mental health surveillance for all survivors of childhood, adolescent, and young adult cancers at every follow-up visit and prompt referral to mental health specialists when problems are identified. Overall, the recommendations reflect the necessity of mental health surveillance as part of comprehensive survivor-focused health care. [ABSTRACT FROM AUTHOR]

The brain is highly vulnerable to neurotoxic agents during the prime learning period of a child's life. Paediatric patients with brain tumours who are treated with cranial radiation therapy (CRT) often go on to develop neurocognitive deficits, which are reflected in poor academic achievement and impaired memory, attention and processing speed. The extent of these delayed effects varies with radiation dose, brain volume irradiated, and age at treatment, and might also be influenced by genetic factors and individual susceptibility. CRT-induced impairment involves axonal damage and disruption of white matter growth, and can affect brain structures implicated in memory function and neurogenesis, such as the hippocampus. In this article, we review the underlying mechanisms and clinical consequences of CRT-induced neurocognitive damage in survivors of paediatric brain tumours. We discuss the recent application of neuroimaging technologies to identify white matter injury following CRT, and highlight new radiation techniques, pharmacological and neurological interventions, as well as rehabilitation programmes that have potential to minimize neurocognitive impairment following CRT. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lung cancer accounts for the largest absolute risk of second malignancies among Hodgkin lymphoma (HL) survivors. However, no population-based studies have compared overall survival (OS) between HL survivors who developed nonsmall cell lung cancer (HL-NSCLC) versus patients with first primary NSCLC (NSCLC-1). METHODS: The authors compared the OS of 178,431 patients who had NSCLC-1 and 187 patients who had HL-NSCLC (among 22,648 HL survivors), accounting for sex, race, sociodemographic status, calendar year, and age at NSCLC diagnosis, and NSCLC histology and stage. All patients were reported to the population-based Surveillance, Epidemiology, and End Results Program. Hazard ratios (HRs) were derived from a Cox proportional hazards model. RESULTS: Although the NSCLC stage distribution was similar in both groups (20% localized, 30% regional, and 50% distant), HL survivors experienced significantly inferior stage-specific OS. For patients with localized, regional, and distant stage NSCLC, the HRs (95% confidence interval [CI]) for death among HL survivors were 1.60 (95% CI, 1.08-2.37; P < .0001), 1.67 (95% CI, 1.26-2.22; P = .0004), and 1.31 (95% CI, 1.06-1.61; P = .013), respectively. Among HL-NSCLC patients, significant associations were observed between more advanced NSCLC stage and the following variables: younger age at HL diagnosis ( P = .003), younger age at NSCLC diagnosis ( P = .048), and longer latency between HL and NSCLC diagnoses ( P = .015). CONCLUSIONS: Compared with patients who had de novo NSCLC, HL survivors experienced a significant 30% to 60% decrease in OS after an NSCLC diagnosis. Further research is needed to not only elucidate the clinical-biologic underpinnings of NSCLC after HL, including the influence of previous HL treatment, but also to define the role of lung cancer screening in selected patients. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to examine long‐term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane‐containing clinical trials. Methods: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana‐Farber Cancer Institute 95‐01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow‐up events were assessed with cumulative incidence, Cox regression, and Fine‐Gray methods. Results: In randomized trials (cumulative prescribed doxorubicin dose, 100‐360 mg/m2; median follow‐up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63‐1.13), second cancers (HR, 1.19; 95% CI, 0.62‐2.30), all‐cause mortality (HR, 1.07; 95% CI, 0.78‐1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41‐5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450‐600 mg/m2; median follow‐up, 16.6‐18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20‐year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2) was 1.6% (vs 0% in P9754; P =.13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P =.02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P =.35). Conclusions: Dexrazoxane did not appear to adversely affect long‐term mortality, event‐free survival, or second cancer risk. Extended follow‐up from pediatric dexrazoxane‐containing trials suggested no adverse impact of dexrazoxane on all‐cause mortality or second cancer risk. Dexrazoxane was associated with a potential reduction in serious cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

As the number of cancer survivors grows because of advances in therapy, it has become more important to understand the long-term complications of these treatments. This article presents the current knowledge of adverse cardiovascular effects of radiotherapy to the chest. Emphasis is on clinical presentations, recommendations for follow-up, and treatment of patients previously exposed to irradiation. Medline™ literature searches were performed, and abstracts related to this topic from oncology and cardiology meetings were reviewed. Potential adverse effects of mediastinal irradiation are numerous and can include coronary artery disease, pericarditis, cardiomyopathy, valvular disease and conduction abnormalities. Damage appears to be related to dose, volume and technique of chest irradiation. Effects may initially present as subclinical abnormalities on screening tests or as catastrophic clinical events. Estimates of relative risk of fatal cardiovascular events after mediastinal irradiation for Hodgkin''s disease ranges between 2.2 and 7.2 and after irradiation for left-sided breast cancer from 1.0 to 2.2. Risk is life long, and absolute risk appears to increase with length of time since exposure. Radiation-associated cardiovascular toxicity may in fact be progressive. Long-term cardiac follow-up of these patients is therefore essential, and the range of appropriate cardiac screening is discussed, although no specific, evidence-based screening regimen was found in the literature. [Copyright &y& Elsevier]

• Radiation-related late cardiac disease risk is updated for the Childhood Cancer Survivor Study using enhanced dosimetry. • Consistent with previous findings, late cardiac disease risk increases with D m ≥ 10 Gy, V 20 ≥ 0.1%, and V 5 , V 20 = 0 % ≥ 50%. • Risks are significantly (P < 0.05) higher than previously estimated for survivors with D m in the range of 20–29.9 Gy. • Risks are significantly (P < 0.05) higher than previously estimated for survivors with V 20 in the range of 30–79.9%. We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (H Atlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (H Hybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort. We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with H Hybrid and mean heart dose (D m), percent volume receiving ≥ 20 Gy (V 20) and ≥ 5 Gy with V 20 = 0 (V 5 , V 20 = 0 % ) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3–5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with D m , V 20 , and V 5 , V 20 = 0 % (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, D m was also considered as a continuous variable. Consistent with previous findings with H Atlas , reevaluation using H Hybrid dosimetry found that, D m ≥ 10 Gy, V 20 ≥ 0.1%, and V 5 , V 20 = 0 % ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for D m in the category of 20 to 29.9 Gy and V 20 in the category of 30% to 79.9%. When changes in the linear dose–response relationship for D m were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy. These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT. [ABSTRACT FROM AUTHOR]