Impact of Volumetric Dosimetry on the Projected Cost of Radiation-Related Late Effects Screening After Childhood Cancer: A Real-World Cohort Analysis.

BACKGROUND: Screening guidelines for childhood cancer survivors treated with radiation currently rely on broad anatomic irradiated regions (IR) to determine risk for late effects. However, contemporary radiotherapy techniques use volumetric dosimetry (VD) to define organ-specific exposure, which supports more specific screening recommendations that could be less costly. PATIENTS AND METHODS: This was a cross-sectional study of 132 patients treated with irradiation at Children's Hospital Los Angeles from 2000 to 2016. For 5 key organs (cochlea, breast, heart, lung, and colon), radiation exposure was determined retrospectively using both IR and VD methods. Under each method, Children's Oncology Group Long-Term Follow-Up Guidelines were used to identify organs flagged for screening and recommended screening tests. Projected screening costs incurred under each method were computed through age 65 using insurance claims data. RESULTS: Median age at the end of treatment was 10.6 years (range, 1.4-20.4). Brain tumor was the most common diagnosis (45%) and head/brain the most common irradiated region (61%). For all 5 organs, use of VD rather than IR resulted in fewer recommended screening tests. This led to average cumulative estimated savings of $3769 (P = .099), with significant savings in patients with CNS tumors (P = .012). Among patients with savings, average savings were $9620 per patient (P = .016) and significantly more likely for females than males (P = .027). CONCLUSION: Use of VD to enhance precision of guideline-based screening for radiation-related late effects permits fewer recommended screening tests and generates cost-savings.

A comprehensive review of 30 years of pediatric clinical trial radiotherapy dose constraints.

BACKGROUND: Radiation therapy normal tissue dose constraints are critical when treating pediatric patients. However, there is limited evidence supporting proposed constraints, which has led to variations in constraints over the years. In this study, we identify these variations in dose constraints within pediatric trials both in the United States and in Europe used in the past 30 years. PROCEDURE: All pediatric trials from the Children's Oncology Group website were queried from inception until January 2022 and a sampling of European studies was included. Dose constraints were identified and built into an organ-based interactive web application with filters to display data by organs at risk (OAR), protocol, start date, dose, volume, and fractionation scheme. Dose constraints were evaluated for consistency over time and compared between pediatric US and European trials RESULTS: One hundred five closed trials were included-93 US trials and 12 European trials. Thirty-eight separate OAR were found with high-dose constraint variability. Across all trials, nine organs had greater than 10 different constraints (median 16, range 11-26), including serial organs. When comparing US versus European dose tolerances, the United States constraints were higher for seven OAR, lower for one, and identical for five. No OAR had constraints change systematically over the last 30 years. CONCLUSION: Review of pediatric dose-volume constraints in clinical trials showed substantial variability for all OAR. Continued efforts focused on standardization of OAR dose constraints and risk profiles are essential to increase consistency of protocol outcomes and ultimately to reduce radiation toxicities in the pediatric population.

Late effects of radiation therapy in pediatric patients and survivorship.

Advances in multimodality therapy have led to childhood cancer cure rates over 80%. However, surgery, chemotherapy, and radiotherapy may lead to debilitating or even fatal long-term effects among childhood survivors beyond those inflicted by the primary disease process. It is critical to understand, mitigate, and prevent these late effects of cancer therapy to improve the quality of life of childhood cancer survivors. This review summarizes the various late effects of radiotherapy and acknowledges the Pediatric Normal Tissue Effects in the Clinic (PENTEC), an international collaboration that is systematically analyzing the association between radiation treatment dose/volume and consequential organ toxicities, in developing children as a basis to formulate recommendations for clinical practice of pediatric radiation oncology. We also summarize initiatives for survivorship and surveillance of late normal tissue effects related to radiation therapy among long-term survivors of childhood cancer treated in the past.

How low can you go? A CBCT dose reduction study.

PURPOSE: Cone beam computed tomography (CBCT) is often used for patient setup based solely on bony anatomy. The goal of this work was to evaluate whether CBCT dose can be lowered to the level of kV image pair doses when used for bony anatomy-based IGRT without compromising positioning accuracy. METHODS: An anthropomorphic phantom was CT scanned in the head, head and neck, chest, and pelvis regions and setup on the linear accelerator couch with the isocenter near the planned location. Cone beam computed tomographies were performed with the standard "full dose" protocol supplied by the linac vendor. With sequentially lowering the dose, three-dimensional (3D) matching was performed for each without shifting the couch. The standard kV image pair protocol for each site was also used to image the phantoms. For all studies, six degrees of freedom was included in the 2D or 3D matching to the extent they could be employed. Imaging doses were determined in air at isocenter following the TG-61 formalism. RESULTS: Cone beam computed tomography dose was reduced by 81-98% of the standard CBCT protocol to nearly that of the standard kV image pair dose for each site. Relative to the standard CBCT shift values, translational shifts were within 0.3 and 1.6 mm for all sites, for the reduced dose CBCT and kV image pair, respectively. Rotational shifts were within 0.2 degree and 0.7 degrees for all sites, for the reduced dose CBCTs and kV image pair, respectively. CONCLUSION: For bony anatomy-based image guidance, CBCT dose can be reduced to a value similar to that of a kV image pair with similar or better patient positioning accuracy than kV image pair alignment. Where rotations are important to correct, CBCT will be superior to orthogonal kV imaging without significantly increased imaging dose. This is especially important for image guidance for pediatric patient treatments.

AAPM MEDICAL PHYSICS PRACTICE GUIDELINE 2.b.: Commissioning and quality assurance of X-ray-based image-guided radiotherapy systems.

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized.

Practice patterns and recommendations for pediatric image-guided radiotherapy: A Children's Oncology Group report.

This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.

The relationship between ventricular volume and whole-brain irradiation dose in central nervous system germ cell tumors.

BACKGROUND: Advanced irradiation techniques, including intensity-modulated radiation therapy (IMRT), aim to limit irradiation to adjoining tissues by conforming beams to a well-defined volume. In intracranial germinomas, whole-ventricular IMRT decreases the volume of irradiation to surrounding parenchyma. This study examined the relationship between ventricular volume and radiation dose to surrounding tissue. PROCEDURE: We retrospectively reviewed age, sex, ventricular and brain volume, ventricular dose, and volume of brain that received 12 Gy (V12) for patients diagnosed with germ cell tumors at our institution treated with whole-ventricular IMRT between 2002 and 2016. Variables were assessed for correlation and statistical significance. RESULTS: Forty-seven patients were analyzed. The median whole-ventricular irradiation dose was 24 Gy with a median boost dose of 30 Gy. The median ventricular volume was 234.3 cm3 , and median brain volume was 1408 cm3 . There was no significant difference between mean ventricular volume of suprasellar versus pineal tumors (P = .95). The median V12 of the brain, including the ventricles, was 58.9%. The strongest correlation was between ventricular volume and V12, with an r2 (coefficient of determination) of .47 (P < .001). Multiple regression analysis indicated that total boost dose and boost planning target volume significantly predicted V12 (P < .001). CONCLUSIONS: Although whole-ventricular IMRT limited irradiation to surrounding tissue in our cohort, a significant percentage of the brain received at least 12 Gy. This study suggests that there is a positive correlation between ventricular volume and the volume of brain parenchyma receiving at least 12 Gy with an important contribution from the boost phase of treatment.

Acute toxicity of craniospinal irradiation with volumetric-modulated arc therapy in children with solid tumors.

BACKGROUND: Craniospinal irradiation (CSI) is an important part of curative radiation therapy (RT) for many types of pediatric brain or solid tumors. After conventional CSI, long term survivors may experience sequelae due to unintended dose to normal tissue. Volumetric modulated arc therapy (VMAT) CSI reduces off-target doses at the cost of greater complexity and error risk, and we describe our initial experience in a group of pediatric patients with solid tumors presenting with disseminated or recurrent disease. PROCEDURE: Pediatric patients with brain tumors were identified at Children's Hospital Los Angeles from 2013 to 2015. Clinical characteristics, acute toxicity, and radiotherapy data were abstracted from their medical records. We identified 19 patients who received VMAT CSI. Quality assurance was performed with a cylindrical detector array and ion chamber measurements at the arc junctions. RESULTS: Patients had medulloblastoma or supratentorial primitive neuro-ectodermal tumor (n = 14, 11 high risk), germ cell tumors (two), relapsed neuroblastoma (two), and atypical teratoid/rhabdoid tumor (one). The most common acute toxicity was hematologic, including leukopenia (11% grade [Gr] 2, 26% Gr 3, and 63% Gr 4), anemia (89% Gr 2), and thrombocytopenia (16% Gr 1-2, 26% Gr 3, and 37% Gr 4). Despite leukopenia, we encountered only two Gr 3 infections (urinary tract and lung). The majority required blood products (89% red blood cells and 68% platelets). Weight loss was also common (47% Gr 1 and 26% Gr 2). CONCLUSIONS: VMAT CSI, along with chemotherapy and anesthesia, is feasible with supportive care. Daily image-guided RT improves accuracy and reduces the risk of spinal cord overdose without increasing treatment time. Further research is needed to determine whether reducing doses to organs, such as thyroid, heart, or hippocampus, offsets the risk of increased volume of low-dose irradiation.

Sensitivity study of an automated system for daily patient QA using EPID exit dose images.

The dosimetric consequences of errors in patient setup or beam delivery and anatomical changes are not readily known. A new product, PerFRACTION (Sun Nuclear Corporation), is designed to identify these errors by comparing the exit dose image measured on an electronic portal imaging device (EPID) from each field of each fraction to those from baseline fraction images. This work investigates the sensitivity of PerFRACTION to detect the deviation caused by these errors in a variety of realistic scenarios. Integrated EPID images were acquired in clinical mode and saved in ARIA. PerFRACTION automatically pulled the images into its database and performed the user-defined comparison. We induced errors of 1 mm and greater in jaw, multileaf collimator (MLC), and couch position, 1° and greater in collimation rotation (patient yaw), 0.5-1.5% in machine output, rail position, and setup errors of 1-2 mm shifts and 0.5-1° roll rotation. The planning techniques included static, intensity modulated radiation therapy (IMRT) and VMAT fields. Rectangular solid water phantom or anthropomorphic head phantom were used in the beam path in the delivery of some fields. PerFRACTION detected position errors of the jaws, MLC, and couch with an accuracy of better than 0.4 mm, and 0.5° for collimator rotation error and detected the machine output error within 0.2%. The rail position error resulted in PerFRACTION detected dose deviations up to 8% and 3% in open field and VMAT field delivery, respectively. PerFRACTION detected induced errors in IMRT fields within 2.2% of the gamma passing rate using an independent conventional analysis. Using an anthropomorphic phantom, setup errors as small as 1 mm and 0.5° were detected. Our work demonstrates that PerFRACTION, using integrated EPID image, is sensitive enough to identify positional, angular, and dosimetric errors.

Executive summary of AAPM Report Task Group 113: Guidance for the physics aspects of clinical trials.

The charge of AAPM Task Group 113 is to provide guidance for the physics aspects of clinical trials to minimize variability in planning and dose delivery for external beam trials involving photons and electrons. Several studies have demonstrated the importance of protocol compliance on patient outcome. Minimizing variability for treatments at different centers improves the quality and efficiency of clinical trials. Attention is focused on areas where variability can be minimized through standardization of protocols and processes through all aspects of clinical trials. Recommendations are presented for clinical trial designers, physicists supporting clinical trials at their individual clinics, quality assurance centers, and manufacturers.

Radiotherapy after high-dose chemotherapy with autologous hematopoietic cell rescue: Quality assessment of Head Start III.

BACKGROUND: The use of high-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) in Head Start III is a potentially curative approach for the management of young children with central nervous system neoplasms. We report the potential influence of quality and timing of radiation therapy on the survival of patients treated on the study. PROCEDURE: Between 2003 and 2009, 220 children with newly diagnosed central nervous system neoplasms were enrolled on the study. Radiation therapy was indicated following AuHCR for children between 6 and 10 years old or those younger than 6 years with residual tumor preconsolidation. Records were received for 42 patients and reviewed to determine adherence to protocol treatment volume and dose guidelines. Of these patients, seven were irradiated prior to consolidation, and additional four patients who initially avoided radiation therapy after AuHCR were subsequently treated at relapse. RESULTS: Of the 31 patients who were fully evaluable, 2 refused radiation therapy until recurrence and 4 progressed between recovery from AuHCR and radiation therapy. Of the remaining 25 patients, 8 had violations in their indication, dose, or treatment volume. All violations occurred in patients under 6 years of age. Two patients could have avoided radiation therapy. There were 6 violations in the 23 patients who received radiation therapy for guideline indications. CONCLUSION: All protocol violations occurred in patients under 6 years of age and were associated with decreased overall survival as was the time to start radiotherapy of greater than 11 weeks. When indicated, starting radiation therapy soon after neutrophil and platelet recovery may improve the outcome for these high-risk children.

A quantitative analysis of craniopharyngioma cyst expansion during and after radiation therapy and surgical implications.

OBJECTIVE When complete resection of craniopharyngioma is not achievable or the sequelae are prohibitive, limited surgery and radiation therapy have demonstrated excellent local disease control while minimizing treatment-related sequelae. When residual tissue exists, there is a propensity for further cyst development and expansion during and after radiation therapy. This can result in obstructive hydrocephalus, visual changes, and/or clinical decline. The authors present a quantitative analysis of cyst expansion during and after radiotherapy and examine how it affected subsequent management. METHODS The authors performed an institutional review board-approved retrospective study of patients with histologically confirmed craniopharyngioma treated between 2000 and 2015 with surgery and intensity-modulated radiation therapy (IMRT) at a single institution. Volumetric measurements of cyst contours were generated by radiation oncology treatment planning software postoperatively, during IMRT, and up to 12 months after IMRT. Patient, tumor, and treatment-related variables were collected until the last known follow-up and were analyzed. RESULTS Twenty-seven patients underwent surgery and IMRT. The median total radiation dose was 54 Gy. Of the 27 patients, 11 patients (40.7%) demonstrated cyst expansions within 1 year of IMRT. Of note, all tumors with cyst expansion were radiographically Puget Grade 2. Maximal cyst expansion peaked at 4.27 months following radiation therapy, with a median volume growth of 4.1 cm3 (mean 9.61 cm3) above the postoperative cyst volume. Eight patients experienced spontaneous cyst regression without therapeutic intervention. Three patients experienced MRI-confirmed cyst enlargement during IMRT, all of whom required adaptive planning to ensure adequate coverage of the entire tumor volume. Two of these 3 patients required ventriculoperitoneal shunt placement and additional intervention. One underwent additional resection, and the other had placement of an intracystic catheter for aspiration and delivery of intracystic interferon within 12 months of completing IMRT. All 3 patients now have stable disease. CONCLUSIONS Craniopharyngioma cyst expansion occurred in approximately 40% of the patients during or after radiotherapy. In the majority of patients, cyst expansion was a self-limiting process and did not confer a worse outcome. During radiotherapy, cyst expansion may be apparent on image-guided radiation therapy. Adaptive IMRT planning may be required to ensure that the intended IMRT dose covers the entire tumor and cyst volume. The sequelae of cyst expansion include progressive hydrocephalus, which may be treated with a shunt. For patients with solitary cyst expansion, cyst aspiration and/or intracystic interferon may result in disease control.

Pulmonary outcomes in patients with Hodgkin lymphoma treated with involved field radiation.

BACKGROUND: Abnormalities in pulmonary function tests (PFT) and clinical symptoms have been reported in up to one third of patients with Hodgkin lymphoma (HL) treated with irradiation. The purpose of this study is to describe the prevalence of pulmonary complications in HL patients treated using contemporary protocols. PROCEDURES: Eligible patients at Children's Hospital Los Angeles from 1999 to 2009 were identified from the radiation oncology database. Clinical features, radiographic findings, PFT, and radiation details were retrospectively ascertained. RESULTS: The median age at diagnosis of 65 patients with HL was 13.6 years and the median follow-up was 3.7 years. The median prescribed radiation dose was 21 Gy. The prevalence of clinical symptoms was low: chronic cough (3%), dyspnea (9.2%), and supplemental oxygen requirement (1.5%). Radiological interstitial lung changes were observed in 31% of the patients. PFT results following irradiation were available in 38 patients. Forced expiratory volume in 1 second (FEV1) and forced expiratory flow 25-75% (FEF25-75%) were decreased in 13% and 11% of patients respectively. Residual volume (RV) was elevated in 21%. Total Lung capacity (TLC) was decreased in 8%. Age at irradiation (P = 0.004), maximum lung dose (P = 0.03), and volume of lung receiving >25 Gy were associated with development of adverse pulmonary outcomes on univariate analysis. On multivariate analysis, older age was associated with worse outcomes. CONCLUSION: In survivors of pediatric HL, involved field irradiation was accompanied by a low prevalence of pulmonary symptoms but substantial subclinical dysfunction. Older age at irradiation was associated with worse pulmonary outcomes.

A retrospective analysis of recurrent intracranial ependymoma.

BACKGROUND: Recurrence occurs in almost 50% of patients with intracranial ependymoma, and their outcome following recurrence is poor. METHODS: We retrospectively reviewed the medical records of 22 patients with intracranial ependymoma and subsequent relapse(s) (59 recurrences) treated at Children's Hospital Los Angeles or New York University between January 1997 and December 2012. RESULTS: Median duration of follow-up was 52 months (7-171 months). Median age at initial diagnosis was 4 years (0.3-19 years) with 8 patients younger than 3 years at presentation. Eleven patients had anaplastic and 11 cellular pathologies. Eighteen patients had infratentorial tumors at diagnosis and 3 (all infratentorial) had metastatic spinal cord involvement at presentation. Cerebrospinal fluid involvement was not identified at diagnosis or relapse. Median time to first recurrence was 16 months (1.3 to 115 months). The number of recurrences in each patient ranged from 1 to 9 (median = 2). Thirty-seven recurrences (63%) were detected asymptomatically by surveillance imaging. Fifteen recurrences (26%) arose outside the initial tumor site. Recurrences were treated by surgical resection (45), with irradiation (30), and with various oral chemotherapies (23) with (7) or without (16) conventional chemotherapy. The 5 and 10 year overall survival rates from first recurrence were 0.37 ± 0.14 and 0.25 ± 0.14. CONCLUSION: Prolonged (5-10 year) survival from first relapse was noted in over one-quarter of our patients. It remains unclear whether early radiographic diagnosis, differing treatment modalities beyond radical surgical resection or possibly unrecognized biological differences contributed towards this prolonged survival.

Reporting Standards for Complication Studies of Radiation Therapy for Pediatric Cancer: Lessons From PENTEC.

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.

Predictive Factors Associated With Radiation Myelopathy in Pediatric Patients With Cancer: A PENTEC Comprehensive Review.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

Radiation Dose-Volume-Response Relationships for Adverse Events in Childhood Cancer Survivors: Introduction to the Scientific Issues in PENTEC.

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.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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 (EQD22; assuming α/ß 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 EQD22 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). CONCLUSIONS: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 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.

Toward Systematic Assessment and Improvement of Radiation Therapy Plan Quality of Cooperative Group Trial Submissions: A Report From the Children's Oncology Group.

PURPOSE: This study evaluates the quality of plans used for the treatment of patients in the Children's Oncology Group study ACNS1123. Plan quality is quantified based on a scoring system specific to the protocol. In this way, the distribution of plan quality scores is determined that can be used to identify plan quality issues for this study and for future plan quality improvement. METHODS AND MATERIALS: ACNS1123 stratum 1 patients (70) were evaluated. This included 50 photon and 20 proton plans. Digital Imaging and Communications in Medicine (DICOM) structure and dose data were obtained from the Children's Oncology Group. A commercially available plan quality scoring algorithm was used to create a scoring system we designed using the protocol dosimetric requirements. The whole ventricle and boost planning target volumes (PTVs) could earn a maximum of 70 points, whereas the organs at risk could earn 30 points (total maximum score of 100 points). The scoring algorithm adjusted scores based on the difficulty in achieving the structure dose requirements, which depended on the proximity of the PTVs and the dose gradients achieved relative to the organs at risk. The distribution of plan scores was used to determine the mean, median, and range of scores. RESULTS: The median adjusted plan quality scores for the 20 proton and 50 photon plans were 83.3 and 86.9, respectively. The range of adjusted scores (maximum to minimum) was 50 points. The average score adjustment was 7.4 points. Photon and proton plans performed almost equally. Average plan quality by individual structure revealed that the brain stem, PTV boost, and cochlea lost the most points. CONCLUSIONS: This report is the first to systematically analyze overall radiation therapy plan quality scores for an entire cohort of patients treated in a cooperative group clinical trial. The methodology demonstrated a large variation in plan quality in this trial. Future clinical trials could potentially use this method to reduce plan quality variability, which may improve outcomes.