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While FLASH radiation therapy is inspiring enthusiasm to transform the field, it is neither new nor well understood with respect to the radiobiological mechanisms. As FLASH clinical trials are designed, it will be important to ensure we can deliver dose consistently and safely to every patient. Much like hyperthermia and proton therapy, FLASH is a promising new technology that will be complex to implement in the clinic and similarly will require customized credentialing for multi-institutional clinical trials. There is no doubt that FLASH seems promising, but many technologies that we take for granted in conventional radiation oncology, such as rigorous dosimetry, 3D treatment planning, volumetric image guidance, or motion management, may play a major role in defining how to use, or whether to use, FLASH radiotherapy. Given the extended time frame for patients to experience late effects, we recommend moving deliberately but cautiously forward toward clinical trials. In this paper, we review the state of quality assurance and safety systems in FLASH, identify critical pre-clinical data points that need to be defined, and suggest how lessons learned from previous technological advancements will help us close the gaps and build a successful path to evidence-driven FLASH implementation.

Purpose: In the current molecular-targeted cancer treatment era, many new agents are being developed so that optimizing therapy with a combination of radiation and drugs is complex. The use of emerging laboratory technologies to further biological understanding of drug-radiation mechanisms of action will enhance the efficiency of the progression from preclinical studies to clinical trials. In 2017, the National Cancer Institute (NCI) solicited proposals through PAR 16-111 to conduct preclinical research combining targeted anticancer agents in the Cancer Therapy Evaluation Program's portfolio with chemoradiation. Methods and Materials The Preclinical Chemo-Radiotherapy Testing Consortium (PCRTC) was formed with 4 U01 programs supported to generate validated high-quality preclinical data on the effects of molecular therapeutics when added to standard-of-care therapies with a concentration on cancers of the pancreas, lung, head and neck, gastrointestinal tract, and brain. Results The PCRTC provides a rational basis for prioritizing NCI-supported investigational new drugs or agents most likely to have clinical activity with chemoradiotherapy and accelerate the pace at which combined modality treatments with greater efficacy are identified and incorporated into standard treatment practices. Conclusions Herein, we introduce and summarize the course of the PCRTC to date and report 3 preliminary observations from the consortium's work to date.

Despite technological advances in radiotherapy and cancer treatment, patients still experience adverse effects. Proton therapy has emerged as a valuable radiotherapy modality, which can improve treatment outcomes. As normal tissue injury is an important determinant of the outcome, for this review, we analyzed two databases, (i) clinical trials registered in ClinicalTrials.gov and (ii) the literature on proton therapy in PubMed, which shows a steady increase in the number of publications. Most studies in proton therapy registered in the ClinicalTrials.gov with results available are nonrandomized early phase studies, with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organ/sites among cancer patients treated with photons and protons to identify critical issues. Present data demonstrate dosimetric advantages of proton therapy with favorable toxicity profiles and forms the basis for comparative randomized prospective trials. Comparative analysis of recently completed three randomized trials for normal tissue toxicities suggest the following: (i) for early stage non-small-cell lung cancer, no meaningful comparison could be made between stereotactic body radiotherapy and stereotactic body proton therapy due to low accrual (NCT01511081), (ii) for locally advanced non-small-cell lung cancer, comparison of intensity-modulated radiotherapy with passive scattering proton therapy (now largely replaced by "spot-scanned" intensity-modulated proton therapy), proton therapy did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy, and (iii) for locally advanced esophageal cancer proton beam therapy provided a lower total toxicity burden; although it did not improve progression free survival and quality-of-life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering advances in technology, physics, and biology are a continuum and advocate for future trials geared towards accurate precision radiation therapy that needs to be viewed as an iterative process in a defined path towards delivering optimal radiation treatment. A foundational understanding of the radiobiological differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized radiation therapy to a patient or a cohort.

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops-and a final concluding "World Café" on March 29, 2021-focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, and 27 universities. Here we summarize the workshops by first describing the background for the workshops. Participants identified twelve key questions-and collaborative parallel ideas-as the focus of work going forward to advance the field. These were then used to define short-term and longer-term "Blue Sky" goals. In addition, the group determined key success factors for predictive oncology in the context of radiation oncology, if not the future of all of medicine. These are: cross-discipline collaboration, targeted talent development, development of mechanistic mathematical and computational models and tools, and access to high-quality multiscale data that bridges mechanisms to phenotype. The workshop participants reported feeling energized and highly motivated to pursue next steps together to address the unmet needs in radiation oncology specifically and in cancer research generally and that NCI and DOE project goals align at the convergence of radiation therapy and advanced computing.

Due to space requirements and a substantial financial burden, the feasibility of health systems adopting proton therapy has been called into question. However, advances in facility design and treatment delivery have allowed institutions offering proton therapy to reduce footprint while incorporating technological improvements at reduced costs. As the number of centers and patients treated continue to increase, this chapter will review the layout and interface of proton therapy facilities providing a detailed overview of the design, costs and faculty and staff considerations.

Amongst the scientific frameworks powered by the Monte Carlo (MC) toolkit Geant4 (Agostinelli et al., 2003), the TOPAS (Tool for Particle Simulation) (Perl et al., 2012) is one. TOPAS focuses on providing ease of use, and has significant implementation in the radiation oncology space at present. TOPAS functionality extends across the full capacity of Geant4, is freely available to non-profit users, and is being extended into radiobiology via TOPAS-nBIO (Ramos-Mendez et al., 2018). A current "grand problem" in cancer therapy is to convert the dose of treatment from physical dose to biological dose, optimized ultimately to the individual context of administration of treatment. Biology MC calculations are some of the most complex and require significant computational resources. In order to enhance TOPAS's ability to become a critical tool to explore the definition and application of biological dose in radiation therapy, we chose to explore the use of Field Programmable Gate Array (FPGA) chips to speedup the Geant4 calculations at the heart of TOPAS, because this approach called "Reconfigurable Computing" (RC), has proven able to produce significant (around 90x) (Sajish et al., 2012) speed increases in scientific computing. Here, we describe initial steps to port Geant4 and TOPAS to be used on FPGA. We provide performance analysis of the current TOPAS/Geant4 code from an RC implementation perspective. Baseline benchmarks are presented. Achievable performance figures of the subsections of the code on optimal hardware are presented; Aspects of practical implementation of "Monte Carlo on a chip" are also discussed.

In a time of rapid advances in science and technology, the opportunities for radiation oncology are undergoing transformational change. The linkage between and understanding of the physical dose and induced biological perturbations are opening entirely new areas of application. The ability to define anatomic extent of disease and the elucidation of the biology of metastases has brought a key role for radiation oncology for treating metastatic disease. That radiation can stimulate and suppress subpopulations of the immune response makes radiation a key participant in cancer immunotherapy. Targeted radiopharmaceutical therapy delivers radiation systemically with radionuclides and carrier molecules selected for their physical, chemical, and biochemical properties. Radiation oncology usage of “big data” and machine learning and artificial intelligence adds the opportunity to markedly change the workflow for clinical practice while physically targeting and adapting radiation fields in real time. Future precision targeting requires multidimensional understanding of the imaging, underlying biology, and anatomical relationship among tissues for radiation as spatial and temporal “focused biology.” Other means of energy delivery are available as are agents that can be activated by radiation with increasing ability to target treatments. With broad applicability of radiation in cancer treatment, radiation therapy is a necessity for effective cancer care, opening a career path for global health serving the medically underserved in geographically isolated populations as a substantial societal contribution addressing health disparities. Understanding risk and mitigation of radiation injury make it an important discipline for and beyond cancer care including energy policy, space exploration, national security, and global partnerships.

In radiopharmaceutical therapy (RPT), a radionuclide is systemically or locally delivered with the goal of targeting and delivering radiation to cancer cells while minimizing radiation exposure to untargeted cells. Examples of current RPTs include thyroid ablation with the administration of (131)I, treatment of liver cancer with (90)Y microspheres, the treatment of bony metastases with (223)Ra and the treatment of neuroendocrine tumors with (177)Lu-DOTATATE. New RPTs are being developed where radionuclides are incorporated into systemic targeted therapies. To assure that RPT is appropriately implemented, advances in targeting need to be matched with advances in quantitative imaging and dosimetry methods. Currently, radiopharmaceutical therapy is administered by intravenous or locoregional injection and the treatment planning has typically been implemented like chemotherapy, where the activity administered is either fixed or based on a patient’s body weight or body surface area (BSA). RPT pharmacokinetics are measurable by quantitative imaging and are known to vary across patients, both in tumors and normal tissues. Therefore, fixed or weight-based activity prescriptions are not currently optimized to deliver a cytotoxic dose to targets while remaining within the tolerance dose of organs at risk. Methods that provide dose estimates to individual patients rather than to reference geometries are needed to assess and adjust the injected RPT dose. Accurate doses to targets and organs at risk will benefit the individual patients and decrease uncertainties in clinical trials. Imaging can be used to measure activity distribution in vivo and this information can be used to determine patient specific treatment plans where the dose to the targets and organs at risk can be calculated. The development and adoption of imaging-based dosimetry methods is particularly beneficial in early clinical trials. In this work we discuss dosimetric accuracy needs in modern radiation oncology, uncertainties in the dosimetry in RPT and best approaches for imaging and dosimetry of internal radionuclide therapy.

The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide. This novel but unconventional use of radiation to treat COVID-19 prompted the National Cancer Institute, National Council on Radiation Protection and Measurements and National Institute of Allergy and Infectious Diseases to convene a workshop involving a diverse group of experts in radiation oncology, radiobiology, virology, immunology, radiation protection and public health policy. The workshop was held to discuss the mechanistic underpinnings, rationale, and preclinical and emerging clinical studies, and to develop a general framework for use in clinical studies. Without refuting or endorsing LDRT as a treatment for COVID-19, the purpose of the workshop and this review is to provide guidance to clinicians and researchers who plan to conduct preclinical and clinical studies, given the limited available evidence on its safety and efficacy.

In 2018, the National Cancer Institute (NCI) and the NRG Oncology partnered for the first time to host a joint Workshop on Systemic Radiopharmaceutical Therapy (RPT) to specifically address issues and strategies of dosimetry for future clinical trials. The workshop focused on (1) current dosimetric approaches for clinical trials, (2) strategies under development that would provide optimal dose reporting, and (3) future desired/optimized approaches for the new and novel emerging radionuclides and carriers in development. In this proceedings, we review the main approaches that are applied clinically to calculate the absorbed dose: These include absorbed doses calculated over a variety of spatial scales including organ, suborgan, and voxel, all achievable within the Medical Internal Radiation Dose (MIRD) schema (S-value) can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This proceeding will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biological effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We will also discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation-when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

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 role of surgery, chemotherapy, and radiation therapy for retinoblastoma has evolved considerably over the years with the efficacy of intraarterial chemotherapy and the high incidence of secondary malignant neoplasms following radiation therapy. The use of spot scanning intensity-modulated proton therapy may reduce the risk of secondary malignancies. For pediatric nasopharyngeal carcinoma, the current standard of care is induction chemotherapy followed by chemoradiation therapy. For adrenocortical carcinoma, the mainstay of treatment is surgery and chemotherapy. The role of radiation therapy remains to be defined.

Purpose Proton beam radiation therapy (PBT) has been increasingly used to treat pediatric brain tumors; however, limited information exists regarding radiation-induced cerebral microbleeds (CMBs) among these patients. The purpose of this study was to evaluate the incidence, risk factors, and imaging appearance of CMBs in pediatric patients with brain tumors treated with PBT. Materials and Methods A retrospective study was performed of 100 pediatric patients with primary brain tumors treated with PBT. CMBs were diagnosed by examination of serial magnetic resonance imaging scans, including susceptibility-weighted imaging. Radiation therapy plans were analyzed to determine doses to individual CMBs. Clinical records were used to determine risk factors associated with the development of CMBs in these patients. Results The mean age at time of PBT was 8.1 years. The median follow-up duration was 57 months. The median time to development of CMBs was 8 months (mean, 11 months; range, 3-28 months). The percentage of patients with CMBs was 43%, 66%, 80%, 81%, 83%, and 81% at 1 year, 2 years, 3 years, 4 years, 5 years, and >5 years from completion of proton radiation therapy. Most of the CMBs (87%) were found in areas of brain exposed to ≥30 Gy. Risk factors included maximum radiation therapy dose (P = .001), percentage and volume of brain exposed to ≥30 Gy (P = .0004, P = .0005), and patient age at time of PBT (P = .0004). Chemotherapy was not a significant risk factor (P = .35). No CMBs required surgical intervention. Conclusions CMBs develop in a high percentage of pediatric patients with brain tumors treated with proton radiation therapy within the first few years after treatment. Significant risk factors for development of CMBs include younger age at time of PBT, higher maximum radiation therapy dose, and higher percentage and volume of brain exposed to ≥30 Gy. These findings demonstrate similarities with CMBs that develop in pediatric patients with brain tumor treated with photon radiation therapy.

Purpose The purpose of this research was to evaluate the incidence, time to development, imaging patterns, risk factors, and clinical significance of large vessel cerebral vasculopathy in pediatric patients with brain tumors treated with proton radiation therapy. Methods and Materials A retrospective study was performed on 75 consecutive pediatric patients with primary brain tumors treated with proton radiation therapy. Radiation-induced large vessel cerebral vasculopathy (RLVCV) was defined as intracranial large vessel arterial stenosis or occlusion confirmed on magnetic resonance angiography, computed tomographic angiography, catheter angiography, or a combination of these within an anatomic region with previous exposure to proton beam therapy and not present before radiation therapy. Clinical records were used to determine the incidence, timing, radiation dose to the large vessels, and clinical significance associated with the development of large vessel vasculopathy in these patients. Results RLVCV was present in 5 of 75 (6.7%) patients and included tumor pathologic features of craniopharyngioma (n=2), ATRT (n=1), medulloblastoma (n=1), and anaplastic astrocytoma (n=1). The median time from completion of radiation therapy to development was 1.5 years (mean, 3.0 years; range, 1.0-7.5 years). Neither mean age at the time of radiation therapy (5.1 years) nor mean radiation therapy dose to the large vessels (54.5 Gy) was a statistically significant risk factor. Four of the 5 patients with RLVCV presented with acute stroke and demonstrated magnetic resonance imaging evidence of acute infarcts in the expected vascular distributions. Angiography studies demonstrated collateral vessel formation in only 2 of the patients with RLVCV. No patients demonstrated acute hemorrhage or aneurysm. Two patients were treated with pial synangiomatosis surgery. Conclusions RLVCV can occur in pediatric patients with brain tumors treated with proton radiation therapy. Further studies are necessary to determine potential risk factors for large vessel vasculopathy with proton radiation therapy in comparison with conventional photon radiation therapy.

The Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs of the National Cancer Institute (NCI) are congressionally mandated set-aside programs that provide research funding to for-profit small businesses for the development of innovative technologies and treatments that serve the public good. These two programs have an annual budget of $159 million (in 2017) and serve as the NCI's main engine of innovation for developing and commercializing cancer technologies. In collaboration with the NCI's Radiation Research Program, the NCI SBIR Development Center published in 2015-2017 three separate requests for proposals from small businesses for the development of systemic targeted radionuclide therapy (TRT) technologies to treat cancer. TRT combines a cytotoxic radioactive isotope with a molecularly targeted agent to produce an anticancer therapy capable of treating local or systemic disease. This article summarizes the NCI SBIR funding solicitations for the development of TRTs and the research proposals funded through them.

While radiosensitizing chemotherapy has improved survival for several types of cancer, current chemoradiation regimens remain ineffective for many patients and have substantial toxicities. Given the strong need for the development of novel radiosensitizers to further improve patient outcomes, the Radiation Research Program (RRP) and the Small Business Innovation Research (SBIR) in the National Cancer Institute (NCI) issued a Request for Proposals (RFP) through the NCI SBIR Development Center's contracts pathway. We sought to determine the research outcomes for the NCI SBIR Development Center's funded proposals for the development of radiosensitizers. We identified SBIR-funded contracts and grants for the development of radiosensitizers from 2009 to 2018 using the National Institutes of Health (NIH) Reporter database. Research outcomes of the NCI SBIR Development Center-funded proposals were determined using a comprehensive internet search. We searched PubMed, clinicaltrials.gov, company websites and google.com for research articles, abstracts and posters, clinical trials, press releases and other news, related to progress in the development of funded radiosensitizers. To protect the intellectual property of the investigators and small businesses, all information obtained and reported is publicly available. The SBIR Program has funded four contracts and 11 grants for the development of novel radiosensitizers. Two companies have received phase IIb bridge awards. Overall, 50% of companies (6/12) have successfully advanced their investigational drugs into prospective clinical trials in cancer patients, and all but one company are investigating their drug in combination with radiation therapy as described in the NCI SBIR Development Center proposal. To date, only one company has initiated a randomized trial of standard of care with or without their radiosensitizer. In conclusion, the NCI SBIR Development Center has funded the development of novel radiosensitizers leading to clinical trials of novel drugs in combination with radiation therapy. Continued follow-up is needed to determine if any of these novel radiosensitizers produce improved tumor control and/or overall survival.

The ability to physically target radiotherapy using image-guidance is continually improving with photons and particle therapy that include protons and heavier ions such as carbon. The unit of dose deposited is the gray (Gy); however, particle therapies produce different patterns of ionizations, and

We define rare tumors in pediatric oncology arbitrarily as including the following histologies: retinoblastoma, nasopharyngeal carcinoma, desmoid, non-CNS germ cell tumors, liver tumors, pleuropulmonary blastoma (PPB), chordoma, malignant peripheral nerve sheath tumors, and for some the true connective tissue tumors. Relative to adult tumors, practically every tumor in this text could be considered rare but these histologies are rare even within the scope of pediatric care.

BACKGROUND AND PURPOSE: Proton radiotherapy has been increasingly utilized to treat pediatric brain tumors, however, limited information exists regarding radiation necrosis among these patients. Our aim was to evaluate the incidence, timing, clinical significance, risk factors, and imaging patterns of radiation necrosis in pediatric patients with brain tumors treated with proton radiation therapy. MATERIALS AND METHODS: A retrospective study was performed on 60 consecutive pediatric patients with primary brain tumors treated with proton radiation therapy. Radiation necrosis was assessed by examining serial MRIs and clinical records to determine the incidence, timing, risk factors, imaging patterns, and clinical significance associated with the development of radiation necrosis in these patients. Radiation necrosis was defined as areas of new enhancement within an anatomic region with previous exposure to proton beam therapy with subsequent decrease on follow-up imaging without changes in chemotherapy. RESULTS: Thirty-one percent of patients developed radiation necrosis with a median time to development of 5.0 months (range, 3–11 months). Risk factors included multiple chemotherapy agents (>3 cytotoxic agents) and atypical teratoid rhabdoid tumor pathology (P = .03 and P = .03, respectively). The most common imaging patterns were small (median, 0.9 cm) and multifocal (63% of patients) areas of parenchymal enhancement remote from the surgical site. The median time to complete resolution on imaging was 5.3 months (range, 3–12 months). Among patients with imaging findings of radiation necrosis, 25% demonstrated severe symptoms with medical intervention indicated. CONCLUSIONS: Pediatric patients with brain tumors treated with proton radiation therapy demonstrate a high incidence of radiation necrosis and a short time to development of necrosis. Multiple small areas of necrosis are frequently identified on imaging. Exposure to multiple chemotherapy agents was a significant risk factor associated with radiation necrosis in these patients.

Purpose: Atypical teratoid rhabdoid tumor is a rare, embryonal, central nervous system tumor seen predominantly in infancy and childhood. Outcomes are generally dismal, with median survival estimated at 6 months to a year. The purpose of this study was to evaluate proton beam therapy (PBT) outcomes in this population. Materials and Methods: Sixteen patients with a diagnosis of atypical teratoid rhabdoid tumor were treated from November 2007 to January 2013 at the Indiana University Health Proton Therapy Center. All patients were treated with PBT. Fraction sizes of 1.8 Gy/fraction were used to deliver 28 to 33 fractions. Seven patients received craniospinal PBT. There were 12 male and 4 female patients. The median age at diagnosis was 18.5 months (range, 5 months to 39 years). Eight had metastatic disease at diagnosis. Fourteen patients underwent surgery. Fifteen patients received chemotherapy. Results: Median survival follow-up time was 3.18 years (or 38.2 months). The mean overall survival was e...

Purpose: To evaluate the effectiveness and tolerance of reirradiation with proton therapy (PT) in patients with recurrent gliomas. Patients and Methods: Between 2005 and 2012, 20 patients with recurrent gliomas were irradiated with proton therapy at the Indiana University Health Proton Therapy Center. Three had low-grade gliomas (LGGs, World Health Organization grade I/II), 4 had grade III, and 13 had glioblastoma (GBM, World Health Organization grade IV). The median time interval between initial radiation and reirradiation was 17.4, 62.8, and 15.3 months for LGG, grade III gliomas, and GBMs, respectively. The median dose delivered was 30, 59.4, and 54 Gy (RBE) for the low-grade, grade III, and grade IV tumors, respectively. Results: The median follow-up time from reirradiation was 8.3 months (range, 1.4 to 25.3), and 30% of the patients were alive at time of follow-up evaluation. Only 1 patient with an LGG had died. Median overall survival (OS) from the time of the original pathologic diagnosis ...

Objective: Midline and central lesions of the brain requiring conventional radiotherapy (RT) present complex difficulties in dose avoidance to organs at risk (OAR). In either definitive or adjuvant settings, proper RT coverage of these lesions involves unnecessary treatment of large volumes of normal brain. We propose a class solution for these lesions using proton radiotherapy (PrT). Materials and Methods: The records of the Indiana University Health Proton Therapy Center were reviewed for patients presenting between January 1, 2005 and October 1, 2013 with midline central nervous system (CNS) lesions. Twenty-four patients were identified. After Institutional Review Board approval was granted, their dosimetry was reviewed for target volume doses and OAR dose avoidance. Results: For these cases, meningiomas were the most common histology (8 cases), and next most prevalent were craniopharyngiomas (6 cases). The others were various different deep midline brain tumors (10 cases). In all cases, fields formed by vertex and/or anterior/posterior superior oblique PrT beams along the midsagittal plane were used to provide coverage with minimal dose to the brain stem or to the cerebral hemispheres. The median prescribed dose to the planning target volume for treating these patients was 54.0 Gy RBE (range 48.6-62.5) with a mean dose of 53.5 Gy RBE. The average of the mean doses to the brain stems using these fields in the 24 plans was 18.4 Gy RBE (range 0.0-44.7). Similarly, the average of the mean doses to the hippocampi was 15.8 Gy RBE (range 0.0-52.6). Conclusions: We consider these patients to be optimally treated with PrT. The use of modified midsagittal PrT schemas allows for the treatment of midline CNS lesions with sparing of most of the uninvolved brain.

Radiotherapy for low-grade gliomas in children has always been controversial due to the high control rates and long potential timeline for the development of late toxicities. The use of effective cytotoxic regimens like carboplatin and vincristine [1], thioguanine, procarbazine, lomustine, and vincristine (TPCV) [2], and single-agent vinblastine [3, 4] means that radiotherapy may often be delayed to a more favorable age allowing for continued normal development. Many children who are not surgical cases will ultimately need radiotherapy for disease control, and thus conformal treatment methods are required. Merchant et al. demonstrated reduced target margin (1 cm CTV) radiotherapy for low-grade gliomas results in excellent disease control and acceptable rates of vasculopathy [5]. ACNS0221 is evaluating the use of 0.5 cm CTV margins for low-grade gliomas, but has not yet been reported. Optic pathway gliomas (OPGs) represent a special case of low-grade glioma and often require treatment due to threatened vision. The response rate of OPGs with vision symptoms is substantial, with greater than 75% having either stabilization or improvement in vision with radiotherapy [6]. Radiotherapy is potentially curative in 80–90% of low-grade gliomas; however, given the potential for late effects, radiotherapy is often used as a last resort after progression following multiple chemotherapy or targeted therapy regimens or when vision is threatened.

Purpose: To examine the various processes involved and to assess their effects on the accuracy in proton therapy.Methods:Proton therapy involved several processes: (1) Beam commissioning. (2) CT scan of patient. (3) Contouring. (4) Treatment planning. (5) Output factor measurements for each field. (6) Patient setup verification with image guidance. (7) Dose delivery. (8) Neutron dose and proton RBE at the distal edge. Within each step, there are several sub‐processes that each may contribute to the uncertainty in the treatment. By analyzing each of the subprocesseswithin each process, based on measurements or published data, we estimated a % uncertainty to each sub‐process and/or a distance uncertainty (in millimeter) on the proton range. A total uncertainty in proton therapy is estimated. Results: The uncertainties assessed for the various processes are : (1) ±1.5%; (4) ±3.0%, and 1–3mm; (5) ±2.0%; (6) ±2 mm; (7) ±2.0%, ±2mm. The uncertainties in (2) CT, (3) contouring and neutron dose in (8) strongly depend on the location and type of the tumor. On the other hand, the proton RBE at the distal edge in (9) is still debatable and may affect the dose uncertainty from 0–20% depending on which value we want to accept. Thus the overall uncertainty in proton therapy is at least ±4.5% and ±4 mm (by adding the various uncertainties in quadrature), without consideration of processes (2), (3) and (8), and the RBE effect. Conclusions: Due to the complexity in proton therapy and the various factors that may affect the accuracy in proton therapy, it is far more complicated to assess the accuracy in proton therapy. Our preliminary study showed that the accuracy in proton therapy is at least ± 4.5% in dose delivered to a tumor with an uncertainty of ±4mm to the distal edge of the SOBP.

A workshop entitled “Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate” (held in Rockville, MD, September 19, 2016) was organized by the Radiation Research Program and Radiation Oncology Branch of the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), to identify critical research areas and directions that will advance the understanding of radiation-induced fibrosis (RIF) and accelerate the development of strategies to mitigate or treat it. Experts in radiation biology, radiation oncology and related fields met to identify and prioritize the key areas for future research and clinical translation. The consensus was that several known and newly identified targets can prevent or mitigate RIF in pre-clinical models. Further, basic and translational research and focused clinical trials are needed to identify optimal agents and strategies for therapeutic use. It was felt that optimally designed preclinical models are needed to better study biomarkers that predict for development of RIF, as well as to understand when effective therapies need to be initiated in relationship to manifestation of injury. Integrating appropriate endpoints and defining efficacy in clinical trials testing treatment of RIF were felt to be critical to demonstrating efficacy. The objective of this meeting report is to (a) highlight the significance of RIF in a global context, (b) summarize recent advances in our understanding of mechanisms of RIF, (c) discuss opportunities for pharmacological mitigation, intervention and modulation of specific molecular pathways, (d) consider the design of optimal clinical trials for mitigation and treatment and (e) outline key regulatory nonprescriptive frameworks for approval.

Glioblastoma is an aggressive disease characterized by moderate initial response rates to first-line radiation-chemotherapy intervention followed by low poor response rates to second-line intervention. This article discusses novel strategic platforms for the development of radiation-investigational agent combination clinical trials for primary and recurrent glioblastoma in a NCI-NCTN settings with simultaneous analysis of challenges in the drug development process.

Introduction Childhood craniopharyngioma is a complex condition to manage. Survival figures are high but the potential for long-term morbidity is great. There is much debate regarding the best management for these tumours with increasing interest in the use of proton beam therapy. We have therefore reviewed our radiotherapy (RT) practice at Westmead Hospital and the literature regarding the use of protons for these children. Methods Three children have received fractionated stereotactic RT for craniopharyngioma at Westmead Hospital since 2007. Each RT plan was reviewed and additional organs at risk were contoured to enable comparison with published proton data. Results Planning target volume coverage was similar with all modalities: with the conformity index ranging from 0.70 to 0.78 in our patients compared with 0.50–0.84 in the published data. RT dose to temporal lobes, hippocampi and whole brain was also similar with protons and photons. Proton beam therapy may give lower dose to the Circle of Willis than stereotactic RT. Conclusion Currently there is no clear evidence that proton beam therapy will improve survival or reduce morbidity for children with craniopharyngioma. However, proton therapy has the potential to reduce RT dose to the Circle of Willis, which may reduce the risk of future cerebrovascular complications. We propose that more resources should be allocated to ensuring these patients are managed by experienced multidisciplinary teams through the continuum from diagnosis to long-term follow-up.

Purpose: To define the temporofrontal angle (TFA), determine the age and gender-related variability of the TFA, and discuss implications of those findings for radiation therapy (RT). Patients and Methods: Treatment-planning software computed tomography images for 122 patients were analyzed for frontal lobe excursion anteriorly between the orbits, defined as the TFA. The TFA, including its anterior and lateral components, was compared as a function of both age and gender. Results: The TFA decreased linearly in pediatric patients (P

Purpose: Survival rates for children with cancer have increased dramatically over several decades, revealing a host of late effects associated with treatment. Proton therapy promises to reduce late effects because of its ability to better localize dose, but the question is by how much? Pediatric health outcomes must be prospectively studied to determine what the margin of benefit is. To facilitate such research, a consortium consisting of pediatric investigators from the US was formed. The goals of the Pediatric Proton Consortium Registry (PPCR) study are to create a comprehensive database of pediatric patients treated with proton radiation therapy in the United States to be used and accessed by participating institutions, to describe the patterns of follow-up at proton facilities, and to describe the acute and late effects in the children treated with proton therapy. Patients and Methods: REDCap is the platform for the ∼600-field database which was designed to capture baseline, treatment, and fo...

Few data exist on evaluating utilization patterns of radiotherapy (RT) at the end of life (EOL) in children. Metastatic disease in pediatric patients is not pathognomonic for palliative treatment intent; further complicating the issue are complexities surrounding the very select population of children receiving proton therapy (PrT). We compared data for RT and PrT in terms of death rate within 30 days.We performed chart reviews for patients receiving radiation therapy at age ≤21 years treated at Indiana University Health Proton Therapy Center (IUHPTC) between June 2008 and June 2013 and University of Miami Radiation Oncology Department (UM) between June 2000 and June 2013. Included were patients not completing prescribed courses of RT, and those dying within 30 days of therapy. Comparison was made of differences between practice data for PrT and conventional RT.At IUHPTC, 2 children of 272 did not complete their courses and died within 30 days (0.7%). At UM, data are available for 425 children; 9 did not complete their courses and 7 died within 30 days (1.6%). Neither the number of patients who did not complete treatment nor the 30-day death rates (P=.21) for PrT and RT were significantly different.Delivery of RT for children at EOL is complex. Frequency of RT at EOL in children occurs in is2% of cases, and is not significantly less frequent in the proton milieu. This appears to be about an order of magnitude less than in adults.

Objective The purpose of this retrospective study is to determine the dependence of acute skin toxicity on physical parameters associated with the proton beam treatment.

Hypothalamic obesity syndrome can affect brain tumor patients following surgical intervention and irradiation. This syndrome is rare at diagnosis in childhood cancer, but has been reported with relapse of acute lymphoblastic leukemia. Here we present a case of hypothalamic obesity syndrome as the primary presentation of a toddler found to have CNS+ B-cell lymphoblastic lymphoma. Cytogenetic studies on diagnostic cerebrospinal fluid revealed MLL gene rearrangement (11q23). Hyperphagia and obesity dramatically improved following induction and consolidation chemotherapy. We describe a novel presentation of hypothalamic obesity syndrome in CNS B-cell lymphoblastic lymphoma, responsive to chemotherapy.

To assess the potential reduction in breast dose for young girls with Hodgkin's lymphoma (HL) treated with breast-sparing proton therapy (BS-PT) as compared with three-dimensional conformal involved-field photon radiotherapy (3D-CRT).The Clarian Health Cancer Registry was queried for female pediatric patients with the diagnosis of HL who received radiotherapy at the Indiana University Simon Cancer Center during 2006-2009. The original CT simulation images were obtained, and 3D-CRT and BS-PT plans delivering 21 Gy or cobalt gray equivalent (CGE) in 14 fractions were created for each patient. Dose-volume histogram data were collected for both 3D-CRT and BS-PT plans and compared by paired t test for correlated samples.The cancer registry provided 10 female patients with Ann Arbor Stage II HL, aged 10-18 years at the time of treatment. Both mean and maximum breast dose were significantly less with BS-PT compared with 3D-CRT: 0.95 CGE vs. 4.70 Gy (p0.001) and 21.07 CGE vs. 23.11 Gy (p0.001), respectively. The volume of breast receiving 1.0 Gy/CGE and 5.0 Gy/CGE was also significantly less with BS-PT, 194 cm(3) and 93 cm(3), respectively, compared with 790 cm(3) and 360 cm(3) with 3D-CRT (p = 0.009, 0.013).Breast-sparing proton therapy has the potential to reduce unnecessary breast dose in young girls with HL by as much as 80% relative to involved-field 3D-CRT.

The uvsWXY system is implicated in the replication and repair of the bacteriophage T4 genome. Whereas the roles of the recombinase (UvsX) and the recombination mediator protein (UvsY) are known, the precise role of UvsW is unclear. Sequence analysis identifies UvsW as a member of the monomeric SF2 helicase superfamily that translocates nucleic acid substrates via the action of two RecA-like motor domains. Functional homologies to Escherichia coli RecG and biochemical analyses have shown that UvsW interacts with branched nucleic acid substrates, suggesting roles in recombination and the rescue of stalled replication forks. A sequencing error at the 3'-end of the uvsW gene has revealed a second, short open reading frame that encodes a protein of unknown function called UvsW.1. We have determined the crystal structure of UvsW to 2.7A and the NMR solution structure of UvsW.1. UvsW has a four-domain architecture with structural homology to the eukaryotic SF2 helicase, Rad54. A model of the UvsW-ssDNA complex identifies structural elements and conserved residues that may interact with nucleic acid substrates. The NMR solution structure of UvsW.1 reveals a dynamic four-helix bundle with homology to the structure-specific nucleic acid binding module of RecQ helicases.

To demonstrate the dosimetric advantages and disadvantages of standard anteroposterior-posteroanterior (S-AP/PAAAA), inverse-planned AP/PA (IP-AP/PA) and volumetry-modulated arc (VMAT) radiotherapies in the treatment of children undergoing whole-lung irradiation. Each technique was evaluated by means of target coverage and normal tissue sparing, including data regarding low doses. A historical approach with and without tissue heterogeneity corrections is also demonstrated. Computed tomography (CT) scans of 10 children scanned from the neck to the reproductive organs were used. For each scan, 6 plans were created: (1) S-AP/PAAAA using the anisotropic analytical algorithm (AAA), (2) IP-AP/PA, (3) VMAT, (4) S-AP/PANONE without heterogeneity corrections, (5) S-AP/PAPB using the Pencil-Beam algorithm and enforcing monitor units from technique 4, and (6) S-AP/PAAAA[FM] using AAA and forcing fixed monitor units. The first 3 plans compare modern methods and were evaluated based on target coverage and normal tissue sparing. Body maximum and lower body doses (50% and 30%) were also analyzed. Plans 4 to 6 provide a historic view on the progression of heterogeneity algorithms and elucidate what was actually delivered in the past. Averages of each comparison parameter were calculated for all techniques. The S-AP/PAAAA technique resulted in superior target coverage but had the highest maximum dose to every normal tissue structure. The IP-AP/PA technique provided the lowest dose to the esophagus, stomach, and lower body doses. VMAT excelled at body maximum dose and maximum doses to the heart, spine, and spleen, but resulted in the highest dose in the 30% body range. It was, however, superior to the S-AP/PAAAA approach in the 50% range. Each approach has strengths and weaknesses thus associated. Techniques may be selected on a case-by-case basis and by physician preference of target coverage vs normal tissue sparing.

Background Uniquely in children, the existence of leptomeningeal spinal metastases does not confer a uniformly grave prognosis. Although the radiation tolerance of the spinal cord is of significant concern in these cases, the chemo- and radiosensitivity of these lesions argues for an aggressive approach where possible. Methods The records of the Indiana University Health Proton Therapy Center were reviewed for patients undergoing proton beam therapy with curative intent for LSM between January 1, 2004 and July 7, 2012. Patients with microscopic disease only on LP were not included. Particulars of therapy, including dose, field sizes, toxicities, and outcomes were collated. Results Twenty-two children received therapy as described, of median age 5 years (range 1.1–17.1). Patients had medulloblastoma (n = 9), ATRT (n = 4), ependymoma, and PNET (n = 3 each). Five lesions (23%) were chemo-recurrent, though no patient had prior radiation to the spine. Median follow-up was 14 months (range 4–33) for all living patients. Fifteen (68%) children continued to have local control at last follow-up visit. Median dose was 37.8 Gy (range 21.6–54 Gy). Eight patients with chemo-recurrent disease or diffuse cord seeding did poorly, with local control and overall survival achieved in four. The 12-month overall survival was 68% with grade 1 skin erythema as the most frequent toxicity. Conclusions We describe a cohort of LSM patients treated with RT with definitive intent, and the only available data from the proton environment. Durable response is possible for these children in over two-thirds of cases. Significant toxicity was infrequent using proton radiotherapy and these fractionation schemes. Pediatr Blood Cancer 2013;60:1839–1841. © 2013 Wiley Periodicals, Inc.

In patients treated with radical prostatectomy in the prostate-specific antigen (PSA) era, it has been demonstrated that the year of treatment in the PSA era is associated with better pathologic parameters and outcomes, independently of other well-recognized parameters such as clinical stage, pretreatment PSA level, or Gleason score. The purpose of the present study was to study a similar phenomenon with definitive radiotherapy (RT).The inclusion criteria were as follows: clinical Stage T1-T2, available pretreatment PSA level and biopsy Gleason score, treatment delivered before January 2000 with standard fractionation external beam radiotherapy to at least 70 Gy, no adjuvant androgen deprivation (AD), all neoadjuvant AD limited toor =6 months, and a minimum of 3 years of PSA follow-up. A total of 467 cases treated between January 1986 and December 1999 were included. Short-course AD in the adjuvant or neoadjuvant setting foror =6 months was given in 124 cases (27%). The median radiation dose was 74 Gy (range 70.0-78.0). A conformal technique was used in 293 cases (63%). The median follow-up was 62 months (range 37-189). A total of 4931 follow-up PSA levels were available for analysis (average 11 per patient). A multivariate analysis for factors affecting biochemical relapse-free survival rates using the proportional hazards model was performed for all cases using the following variables: age (continuous variable), race (black vs. white), clinical T stage (T1-T2a vs. T2b-T2c), pretreatment PSA (continuous variable), biopsy Gleason score (continuous variable), use of AD (yes vs. no), radiation dose (continuous variable), and year of treatment (continuous variable: 1986-1999).The projected 8-year biochemical relapse-free survival rate was 74%. The projected 5-year biochemical relapse-free survival rate for the 143 patients treated in the 1986-1995 period was 58% vs. 82% for the 324 patients treated in the 1996-1999 period (p0.001). The difference was attributable to a multitude of factors (earlier stage cancer, higher radiation doses, shorter follow-up). To study the confounding effects of these factors on the year of therapy, a multivariate analysis was performed. The multivariate analysis revealed the initial PSA level (p0.001), Gleason score (p0.001), RT dose (p = 0.045), and year of treatment (p0.001) to be independent predictors of outcome. Age (p = 0.41), race (p = 0.14), T stage (p = 0.10), and use of AD (p = 0.58) were not.When controlling for tumor, treatment, and follow-up parameters, the year in which RT was performed was still an independent predictor of outcome, consistent with observations made for radical prostatectomy patients. This indicates a more favorable presentation of localized prostate in current years probably related to a combination of factors such as screening and increased patient awareness leading to earlier diagnosis. Outcome predictions should be based on contemporaneous series.