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In 2010, we published a comprehensive review of our institutional outcomes about treating children with spinal and paraspinal Ewing sarcoma using photon therapy. Multimodality therapy was associated with fair disease control but also with serious toxicity, including a 37% rate of grade 3 or greater toxicity. We therefore sought to assess our more recent experience about treating children with more modern technology and treatment regimens.Between 2010 and 2021, 32 pediatric patients with nonmetastatic spinal and paraspinal Ewing sarcoma were treated at University of Florida and enrolled in a retrospective outcome study. Median age at diagnosis was 9.8 years (range, 2.1-21.8 years). Within the cervical, thoracic, and lumbar spine regions, 3, 22, and 7 tumors arose, respectively. Median maximum tumor diameter was 5 cm (range, 3-19 cm). At diagnosis, 28 of 32 patients had motor, bowel, or bladder deficits. Chemotherapy was delivered according to contemporary North American and European interval-compressed regimens. Before radiation therapy, 14 patients underwent gross total resection, whereas 18 underwent a biopsy or subtotal resection with cord decompression. All patients were treated with proton therapy; 6 with hardware stabilization also received a component of intensity modulated photon therapy. Median prescription dose was 50.4 gray relative biological effectiveness (GyRBE; range, 45-55.8 GyRBE). Median maximum dose to the spinal cord was 50.2 GyRBE (range, 0-54.9 GyRBE).With a median follow-up of 4.1 years (range, 0.7-9.4 years), the 5-year local control, progression-free survival, and overall survival rates were 92%, 79%, and 85%, respectively. Ten of 30 living patients have residual motor, bowel, or bladder deficits. Overall, 22% of patients experienced Common Terminology Criteria for Adverse Events grade 3 late toxicity related to multimodality treatment: kyphosis (n = 4), esophagitis (n = 2), and chronic kidney disease (n = 1). No patients developed grade 4 or greater toxicity, new neurologic deficits, or second malignancy.Modern treatment advances may offer an improved therapeutic ratio for pediatric patients with spinal and paraspinal Ewing sarcoma. With appropriate management, most patients can be cured with recovery of long-term neurologic function and modest side effects.

Purpose: Compared with photon cranial radiation therapy (X-CRT), proton cranial radiation therapy (P-CRT) offers potential advantages in limiting radiation-induced sequalae in the treatment of pediatric brain tumors. This study aims to identify cognitive, functional magnetic resonance and positron emission tomography imaging markers and molecular differences between the radiation modalities. Methods and Materials: Juvenile rats received a single faction of 10 Gy (relative biological effectiveness−weighted dose) delivered with 6 MV X-CRT or at the midspread out Bragg peak of a 100 MeV P-CRT beam. At 3, 6, and 12 months post-CRT, executive function was measured using 5-choice serial reaction time task. At ~12 months post-CRT, animals were imaged with 18F-Flurodeoxy-glucose positron emission tomography imaging followed by functional ex vivo magnetic resonance imaging and stained for markers of neuroinflammation. Results: Irradiated animals had cognitive impairment with a higher number of omissions and lower incorrect and premature responses compared with sham (P ≤ .05). The accuracy of the animals’ X-CRT was less than that of sham (P ≤ .001). No significant difference in rates of cognitive change were found between the radiation modalities. At 12 months post-CRT, glucose metabolism was significantly higher than sham in X-CRT (P = .04) but not P-CRT. Using diffusion tensor imaging, P-CRT brains were found to have higher white matter volume and fiber lengths compared with sham (P < .03). Only X-CRT animals had higher apparent diffusion coefficient values compared with sham (P = .04). P-CRT animals had more connectomic changes compared with X-CRT. Correlative analysis identified several imaging features with cognitive performance. Further-more, microgliosis (P < .05), astrogliosis (P < .01), and myelin thinning (P

Time dependence of relative biological effectiveness (RBE) of carbon ions for skin damage was investigated to answer the question of whether the flat distribution of biological doses within a Spread-Out Bragg peak (SOBP) which is designed based on in vitro cell kill could also be flat for in vivo late responding tissue. Two spots of Indian ink intracutaneously injected into the legs of C3H mice were measured by calipers. An equieffective dose to produce 30% skin contraction was calculated from a dose–response curve and used to calculate the RBE of carbon ion beams. We discovered skin contraction progressed after irradiation and then reached a stable/slow progression phase. Equieffective doses decreased with time and the decrease was most prominent for gamma rays and least prominent for 100 keV/μm carbon ions. Survival parameter of alpha but not beta in the linear-quadratic model is closely related to the RBE of carbon ions. Biological doses within the SOBP increased with time but their distribution was still flat up to 1 year after irradiation. The outcomes of skin contraction studies suggest that (i) despite the higher RBE for skin contracture after carbon ions compared to gamma rays, gamma rays can result in a more severe late effect of skin contracture. This is due to the carbon effect saturating at a lower dose than gamma rays, and (ii) the biological dose distribution throughout the SOBP remains approximately the same even one year after exposure.

Proton therapy is increasingly being used as a radiation therapy modality. There is uncertainty about the biological effectiveness of protons relative to photon therapies as it depends on several physical and biological parameters. Radiation oncology currently applies a constant and generic value for the relative biological effectiveness (RBE) of 1.1, which was chosen conservatively to ensure tumor coverage. The use of a constant value has been challenged particularly when considering normal tissue constraints. Potential variations in RBE have been assessed in several published reviews but have mostly focused on data from clonogenic cell survival experiments with unclear relevance for clinical proton therapy. The goal of this review is to put in vitro findings in relation to clinical observations. Relevant in vivo pathways determining RBE for tumors and normal tissues are outlined, including not only damage to tumor cells and parenchyma but also vascular damage and immune response. Furthermore, the current clinical evidence of varying RBE is reviewed. The assessment can serve as guidance for treatment planning, personalized dose prescriptions, and outcome analysis.

Clinical treatment with protons uses the concept of relative biological effectiveness (RBE) to convert the absorbed dose into an RBE-weighted dose that equals the dose for radiotherapy with photons causing the same biological effect. Currently, in proton therapy a constant RBE of 1.1 is generically used. However, empirical data indicate that the RBE is not constant, but increases at the distal edge of the proton beam. This increase in RBE is of concern, as the clinical impact is still unresolved, and clinical studies demonstrating a clinical effect of an increased RBE are emerging. Within the European Particle Therapy Network (EPTN) work package 6 on radiobiology and RBE, a workshop was held in February 2020 in Manchester with one day of discussion dedicated to the impact of proton RBE in a clinical context. Current data on RBE effects, patient outcome and modelling from experimental as well as clinical studies were presented and discussed. Furthermore, representatives from European clinical proton therapy centres, who were involved in patient treatment, laid out their current clinical practice on how to consider the risk of a variable RBE in their centres. In line with the workshop, this work considers the actual impact of RBE issues on patient care in proton therapy by reviewing preclinical data on the relation between linear energy transfer (LET) and RBE, current clinical data sets on RBE effects in patients, and applied clinical strategies to manage RBE uncertainties. A better understanding of the variability in RBE would allow development of proton treatments which are safer and more effective.

Purpose To investigate the dosimetric impact of changes in the large bowel content during proton therapy (PT) with simultaneous integrated boost (SIB) for locally advanced pancreatic cancer (LAPC). Materials and methods Fifteen patients with LAPC were included in this study. The SIB method was performed using five fields according to our standard protocol. A total dose of 67.5 Gy(relative biological effectiveness [RBE]) was prescribed in 25 fractions using the SIB method. A dose of 45 Gy(RBE) was prescribed for the entire planning target volume (PTV) by using four main fields. The remaining 22.5 Gy(RBE) was prescribed to the PTV excluding for the gastrointestinal tract using one subfield. Five simulated doses were obtained by the forward dose calculations with the Hounsfield units (HU) override to the large bowel to 50, 0, −100, −500, and −1000, respectively. The dose‐volume indices in each plan were compared using the 50 HU plan as a reference. Results At D98 of the clinical target volume (CTV) and spinal cord‐D2cc, when the density of the large bowel was close to that of gas, there were significant differences compared to the reference plan (p

Purpose Boron Neutron Capture Therapy (BNCT) is a form of hadrontherapy based on the selective damage caused by the products of neutron capture in 10B to tumour cells. BNCT dosimetry strongly depends on the parameters of the dose calculation models derived from radiobiological experiments. This works aims at determining an adequate dosimetry for in-vitro experiments involving irradiation of monolayer-cultured cells with photons and BNCT and assessing its impact on clinical settings. M&M Dose calculations for rat osteosarcoma UMR-106 and human metastatic melanoma Mel-J cell survival experiments were performed using MCNP, transporting uncharged particles for KERMA determinations, and secondary particles (electrons, protons, 14C, 4He and 7Li) to compute absorbed dose in cultures. Dose-survival curves were modified according to the dose correction factors determined from computational studies. New radiobiological parameters of the photon isoeffective dose models for osteosarcoma and metastatic melanoma tumours were obtained. Dosimetry implications considering cutaneous melanoma patients treated in Argentina with BNCT were assessed and discussed. Results KERMA values for the monolayer-cultured cells overestimate absorbed doses of radiation components of interest in BNCT. Detailed dose calculations for the osteosarcoma irradiation increased the relative biological effectiveness factor RBE1% of the neutron component in more than 30%. The analysis based on melanoma cases reveals that the use of survival curves based on KERMA leads to an underestimation of the tumour doses delivered to patients. Conclusions Considering detailed dose calculation for in-vitro experiments significantly impact on the prediction of the tumor control in patients. Therefore, proposed methods are clinically relevant.

PURPOSE The stochastic microdosimetric kinetic (SMK) model is one of the most sophisticated and precise models used in the estimation of the relative biological effectiveness of carbon-ion radiotherapy (CRT) and boron neutron capture therapy (BNCT). However, because of its complicated and time-consuming calculation procedures, it is nearly impractical to directly incorporate this model into a radiation treatment-planning system. MATERIALS AND METHODS Through the introduction of Taylor expansion (TE) or fast Fourier transform (FFT), we developed two simplified SMK models and implemented them into the Particle and Heavy Ion Transport code System (PHITS). To verify the implementation, we calculated the photon isoeffective doses in a cylindrical phantom placed in the radiation fields of passive CRT and accelerator-based BNCT. RESULTS AND DISCUSSION Our calculation suggested that both TE-based and FFT-based SMK models can reproduce the data obtained from the original SMK model very well for absorbed doses approximately below 5 Gy, whereas the TE-based SMK model overestimates the original data at higher doses. In terms of computational efficiency, the TE-based SMK model is much faster than the FFT-based SMK model. CONCLUSION This study enables the instantaneous calculation of the photo isoeffective dose for CRT and BNCT, considering their cellular-scale dose heterogeneities. Treatment-planning systems that use the improved PHITS as a dose-calculation engine are under development.

Based on FLUKA, the present study is aimed at calculating the microdosimetric distributions of electron beams (6, 12 and 18 MeV) for radiotherapy as a function of depth in water at a site-size of 1 μm using a tissue-equivalent proportional counter (TEPC). Using the calculated microdosimetric distributions, the depth-specific relative biological effectiveness (RBE) of electron beams used in radiotherapy is calculated based on the theory of dual radiation action (TDRA) and the microdosimetric kinetic model (MKM). The TDRA-based calculation shows the variation of RBE of an electron beam with the absorbed dose and depth in water. In this study, we compared the RBE values calculated based on the TDRA and MKM. The FLUKA-based microdosimetric distributions in water obtained using the pre-calculated electron fluence spectra resulted in an improvement in the computational efficiency by a factor of 110 when compared with a full simulation. Depending on the beam energy and depth of water, RBETDRA was in the range 0.67–0.78. RBEMKM at 10% survival of HSG tumor cells was 0.84, which was nearly independent of the depth and beam energy.

The effect of proton pencil beam scanning in the dose range of 4.5-15 Gy on the radiosensitivity of mice under irradiation in two regions of the Bragg curve was studied according to the criteria of 30-day survival, dynamics of death, and average lifespan of mice. The relative biological effectiveness (RBE) value of protons relative to X-ray radiation before and at the Bragg peak determined by the LD50/30 index was 0.86 and 0.94, respectively, and by the criterion of 30-day survival at a dose of 6.5 Gy it was 0.83 and 0.84, respectively. With similar RBE values for protons in different regions of the Bragg curve, significant differences in the dynamics of the course of radiation sickness were revealed, which indicates different damage to critical systems and organs of animals and the induction of compensatory mechanisms involved in the formation of stress responses at the organismal level.

We proposed a novel tool-a dose linear energy transfer (LET)-volume histogram (DLVH)-and performed an exploratory study to investigate rectal bleeding in prostate cancer treated with intensity modulated proton therapy.The DLVH was constructed with dose and LET as 2 axes, and the normalized volume of the structure was contoured in the dose-LET plane as isovolume lines. We defined the DLVH index, DLv%(d,l) (ie, v% of the structure) to have a dose of ≥d Gy and an LET of ≥l keV/μm, similar to the dose-volume histogram index Dv%. Nine patients with prostate cancer with rectal bleeding (Common Terminology Criteria for Adverse Events grade ≥2) were included as the adverse event group, and 48 patients with no complications were considered the control group. A P value map was constructed by comparison of the DLVH indices of all patients between the 2 groups using the Mann-Whitney U test. Dose-LET volume constraints (DLVCs) were derived based on the P value map with a manual selection procedure facilitated by Spearman's correlation tests. The obtained DLVCs were further cross-validated using a multivariate support vector machine (SVM)-based normal tissue complication probability (NTCP) model with an independent testing data set composed of 8 adverse event and 13 control patients.We extracted 2 DLVC constraints. One DLVC was obtained, Vdose/LETboundary:2.5keVμmat 75 Gy to 3.2keVμmat8.65Gy1.27% (DLVC1), revealing a high LET volume effect. The second DLVC, V(72.2Gy,0keVμm)2.23% (DVLC2), revealed a high dose volume effect. The SVM-based NTCP model with 2 DLVCs provided slightly superior performance than using dose only, with an area under the curve of 0.798 versus 0.779 for the testing data set.Our results demonstrated the importance of rectal "hot spots" in both high LET (DLVC1) and high dose (DLVC2) in inducing rectal bleeding. The SVM-based NTCP model confirmed the derived DLVCs as good predictors for rectal bleeding when intensity modulated proton therapy is used to treat prostate cancer.

Purpose A 5 and 10 μm thin silicon on insulator (SOI) 3D mushroom microdosimeter was used to characterise both the in-field and out-of-field of a 62 MeV proton beam. Methods The SOI mushroom microdosimeter consisted of an array of cylindrical sensitive volumes (SVs), developed by the Centre for Medical Radiation Physics, University of Wollongong, was irradiated with 62 MeV protons at the CATANA (Centro di AdroTerapia Applicazioni Nucleari Avanzate) facility in Catania, Italy, a facility dedicated to the radiation treatment of ocular melanomas. Dose mean lineal energy, ( y D ¯ ), values were obtained at various depths in PMMA along a pristine and spread out Bragg peak (SOBP). The measured microdosimetric spectra at each position were then used as inputs into the modified Microdosimetric Kinetic Model (MKM) to derive the RBE for absorbed dose in a middle of the SOBP 2Gy (RBED ). Microdosimetric spectra were obtained with both the 5 and 10 μm 3D SOI microdosimeters, with a focus on the distal part of the BP. The in-field and out-of-field measurement configurations along the Bragg curve were modelled in Geant4 for comparison with experimental results. Lateral out-of-field measurements were performed to study secondary particles' contribution to normal tissue's dose, up to 12 mm from the edge of the beam field, and quality factor and dose equivalent results were obtained. Results Comparison between experimental and simulation results showed good agreement between one another for both the pristine and SOBP beams in terms of y D ¯ and RBED . Though a small discrepancy between experiment and simulation was seen at the entrance of the Bragg curve, where experimental results were slightly lower than Geant4. The dose equivalent value measured 12 mm from the edge of the target volume was 1.27 ± 0.15 mSv/Gy with a Q ¯ value of 2.52 ± 0.30, both of which agree within uncertainty with Geant4 simulation. Conclusions These results demonstrate that SOI microdosimeters are an effective tool to predict RBED in-field as well as dose equivalent monitoring out-of-field to provide insight to probability of second cancer generation.

Lung is one of the high-risk organs for radiation-induced carcinogenesis, but the risk of secondary lung-cancer development after particle-beam therapy and the underlying mechanism(s) remain to be elucidated. To investigate the effects of particle-beam radiation on adjacent normal tissues during cancer therapy, 7-week-old male and female B6C3F1 mice were irradiated with 0.2-4 Gy of gamma rays (for comparison), carbon ions (290 MeV/u, linear energy transfer 13 keV/µm), or fast neutrons (0.05-1 Gy, mean energy, ∼2 MeV), and lung-tumor development was assessed by histopathology. Mice irradiated with ≥2 Gy of carbon ions or ≥0.2 Gy of neutrons developed lung adenocarcinoma (AC) significantly sooner than did non-irradiated mice. The relative biological effectiveness values for carbon ions for lung AC development were 1.07 for male mice and 2.59 for females, and the corresponding values for neutrons were 4.63 and 4.57. Genomic analysis of lung ACs revealed alterations in genes involved in Egfr signaling. Hyperphosphorylation of Erk and a frequent nuclear abnormality (i.e., nuclear groove) were observed in lung ACs of mice irradiated with carbon ions or neutrons compared with ACs from non-irradiated or gamma-ray-irradiated groups. Our data indicate that the induction of lung AC by carbon ions occurred at a rate similar to that for gamma rays in males and approximately 2-to 3-fold greater than that for gamma rays in females. In contrast, the effect of neutrons on lung AC development was approximately 4- to 5-fold greater than that of gamma rays. Our results provide valuable information concerning risk assessment of radiation-induced lung tumors after particle-beam therapy and increase our understanding of the molecular basis of tumor development.

We have developed physical and biological beam modeling for carbon scanning therapy at the Osaka Heavy Ion Therapy Center (Osaka HIMAK). Carbon beam scanning irradiation is based on continuous carbon beam scanning, which adopts hybrid energy changes using both accelerator energy changes and binary range shifters in the nozzles. The physical dose calculation is based on a triple Gaussian pencil‐beam algorithm, and we thus developed a beam modeling method using dose measurements and Monte Carlo simulation for the triple Gaussian. We exploited a biological model based on a conventional linear‐quadratic (LQ) model and the photon equivalent dose, without considering the dose dependency of the relative biological effectiveness (RBE), to fully comply with the carbon passive dose distribution using a ridge filter. We extended a passive ridge‐filter design method, in which carbon and helium LQ parameters are applied to carbon and fragment isotopes, respectively, to carbon scanning treatment. We then obtained radiation quality data, such as the linear energy transfer (LET) and LQ parameters, by Monte Carlo simulation. The physical dose was verified to agree with measurements to within ±2% for various patterns of volume irradiation. Furthermore, the RBE in the middle of a spread‐out Bragg peak (SOBP) reproduced that from passive dose distribution results to within ±1.5%. The developed carbon beam modeling and dose calculation program was successfully applied in clinical use at Osaka HIMAK.

Purpose To show that intrinsic radiosensitivity varies greatly for protons and carbon (C) ions in addition to photons, and that DNA repair capacity remains important in governing this variability. Methods We measured or obtained from the literature clonogenic survival data for a number of human cancer cell lines exposed to photons, protons (9.9 keV/μm), and C-ions (13.3-77.1 keV/μm). We characterized their intrinsic radiosensitivity by the dose for 10% or 50% survival (D10% or D50% ), and quantified the variability at each radiation quality by the coefficient of variation (COV) in D10% and D50% . We also treated cells with DNA repair inhibitors prior to irradiation to assess how DNA repair capacity affects their variability. Results We found no statistically significant differences in the COVs of D10% or D50% between any of the radiation qualities investigated. The same was true regardless of whether the cells were treated with DNA repair inhibitors, or whether they were stratified into histologic subsets. Even within histologic subsets, we found remarkable differences in radiosensitivity for high LET C-ions that were often greater than the variations in RBE, with brain cancer cells varying in D10% (D50% ) up to 100% (131%) for 77.1 keV/μm C-ions, and non-small cell lung cancer and pancreatic cancer cell lines varying up to 55% (76%) and 51% (78%), respectively, for 60.5 keV/μm C-ions. The cell lines with modulated DNA repair capacity had greater variability in intrinsic radiosensitivity across all radiation qualities. Conclusions Even for cell lines of the same histologic type, there are remarkable variations in intrinsic radiosensitivity, and these variations do not differ significantly between photon, proton or C-ion radiation. The importance of DNA repair capacity in governing the variability in intrinsic radiosensitivity is not significantly diminished for higher LET radiation.

PURPOSE: We sought to investigate the tumor control probability (TCP) of vestibular schwannomas (VS) following single-fraction stereotactic radiosurgery (SRS) or hypofractionated SRS over 2–5 fractions (fSRS). MATERIALS AND METHODS: Studies (PubMed Indexed from 1993 – 2017) were eligible for data extraction if they contained dosimetric details of SRS/fSRS correlated with local tumor control. The rate of tumor control at 5 years (or at 3 years if 5-year data were not available) were collated. Poisson modeling estimated the TCP per equivalent dose in 2 Gy per fraction (EQD2) and in 1, 3, and 5 fractions. RESULTS: Data were extracted from 35 publications containing a total of 5162 patients. TCP modeling was limited by the absence of analyzable data of

The particle irradiation data ensemble (PIDE) is the largest database of cell survival data measured after exposure to ion beams and photon reference radiation. We report here on the updated version of the PIDE database and demonstrate how to investigate generic properties of radiation dose response using these sets of raw data. The database now contains information of over 1100 pairs of photon and ion dose response curves. It provides the originally published raw data of cell survival in addition to given linear quadratic (LQ) model parameters. If available, the raw data were used to derive LQ model parameters in the same way for all experiments. To demonstrate the extent of the database and the variability among experiments we focus on the dose response curves after ion and photon radiation separately in a first step. Furthermore, we discuss the capability and the limitations of the database for analyzing properties of low and high linear energy transfer (LET) radiation response based on multiple experiments. PIDE is freely available to the research community under www.gsi.de/bio-pide.

This study aimed to evaluate the long-term efficacy of proton beam therapy (PBT) for unresectable benign meningiomas at the University of Tsukuba, Japan. From 1986–1998, 10 patients were treated at the Particle Radiation Medical Science Center (PRMSC) with a relative biological effectiveness (RBE) value of 1.0 using an accelerator built for physics experiments. The total dose was compensated with an X-ray in three patients. Following that, from 2002–2017, 17 patients were treated with a RBE value of 1.1 at the Proton Medical Research Center (PMRC) which was built for medical use. At the PRMSC, the total dose ranged from 50.4–66 Gy (median: 54 Gy). During the follow-up, which lasted between 3.8 and 31.6 years (median: 25.1 years), the 5-, 10-, 15-, 20- and 30-year local control rates were 100%, and the 5-, 10-, 15-, 20- and 30-year survival rates were 90, 80, 70, 70 and 36%, respectively. One patient died of brainstem radiation necrosis 5.1 years after PBT. At PMRC, the total dose ranged from 45.0–61.2 GyE, with a median of 50.4 GyE. During the follow-up, which lasted between 3 and 17 years with a median of 10.5 years, the 5-, 10- and 15-year local control rates were 94.1%, and the 5-, 10- and 15-year survival rates were 100, 100 and 88.9%, respectively. Neither malignant transformation nor secondary malignancy was observed, indicating that fractionated PBT may be effective and safely control benign unresectable meningioma even for the lifelong period of time.

Purpose This multi-institutional retrospective study sought to examine the hematologic effects of craniospinal irradiation (CSI) in pediatric patients with medulloblastoma using proton or photon therapy. Methods and Materials Clinical and treatment characteristics were recorded for 97 pediatric patients with medulloblastoma who received CSI without concurrent chemotherapy or with concurrent single-agent vincristine from 2000 to 2017. Groups of 60 and 37 patients underwent treatment with proton-based and photon-based therapy, respectively. Overall survival was determined by Kaplan-Meier curves with log-rank test. Comparisons of blood counts at each timepoint were conducted using multiple t tests with Bonferroni corrections. Univariate and multivariate analyses of time to grade ≥3 hematologic toxicity were performed with Cox regression analyses. Results Median age of patients receiving proton and photon CSI was 7.5 years (range, 3.5-22.7 years) and 9.9 years (range, 3.6-19.5 years), respectively. Most patients had a diagnosis of standard risk medulloblastoma, with 86.7% and 89.2% for the proton and photon cohorts, respectively. Median total dose to involved field or whole posterior fossa was 54.0 Gy/Gy relative biological effectiveness (RBE) and median CSI dose was 23.4 Gy/Gy(RBE) (range, 18-36 Gy/Gy[RBE]) for both cohorts. Counts were significantly higher in the proton cohort compared with the photon cohort in weeks 3 to 6 of radiation therapy (RT). Although white blood cell counts did not differ between the 2 cohorts, patients receiving proton RT had significantly higher lymphocyte counts throughout the RT course. Similar results were observed when excluding patients who received vertebral body sparing proton RT or limiting to those receiving 23.4 Gy. Only photon therapy was associated with decreased time to grade ≥3 hematologic toxicity on univariate and multivariable analyses. No difference in overall survival was observed, and lymphopenia did not predict survival. Conclusions Patients who receive CSI using proton therapy experience significantly decreased hematologic toxicity compared with those receiving photon therapy.

Purpose Stereotactic body radiation therapy (SBRT) to metastatic mediastinal and hilar lymphadenopathy (MHL) is challenging owing to the proximity of centrally located organs-at-risk. As limited data exist on the safety and efficacy of SBRT for MHL, a retrospective review of clinical outcomes was conducted from a large academic center. Methods and Materials Eligible patients received SBRT to MHL between 2014 to 2019 for the following indications: oligometastases, oligoprogression, or local control of a dominant area of progression. The primary endpoint was grade ≥3 toxicity (Common Terminology Criteria for Adverse Events, version 5.0). The cumulative incidence function evaluated local failure (LF) and starting or changing systemic therapy (SCST). Kaplan-Meier methodology estimated progression-free survival (PFS) and overall survival (OS). Results Fifty-two patients (84 metastases) were included. Median follow-up was 20 months. Primary cancer sites included kidney (53.8%), lung (13.4%), breast (7.7%), and other (25.1%). Indications for SBRT were oligoprogression (n = 35; 67.3%), oligometastases (n = 10; 19.2%), or local failure of a dominant area of progression (n = 7; 13.5%). The majority (n = 31; 59.6%) received SBRT to a single lymph node metastasis. Median SBRT dose was 35 Gy (range, 30-50 Gy) with a median biologically effective dose of 59.5 Gy (range, 48-100 Gy). All treatments were in 5 fractions. Seven grade ≥3 toxicities were experienced by 6 patients (11.5%) and were mostly transient (5/7; 71%). There was a single (1.9%) grade 5 toxicity (radiation pneumonitis). The cumulative incidence of LF was 9.0% at 2 years. The cumulative incidence of SCST was 33.2% and 57.1% at 1 and 2 years, respectively. Median PFS was 4.0 months (95% confidence interval, 2.8-7.3) and median OS was 31.7 months (95% confidence interval, 23.8-87.5). Conclusions In one of the largest single institutional series of SBRT for MHL, moderate rates of grade ≥3 toxicity were observed, although the majority were transient. This treatment resulted in low LF rates and potentially delayed SCST for many patients.

Purpose To investigate the impact of different setup methods, vertebral body matching (VM), diaphragm matching (DM), and marker matching (MM), on the dose distribution in proton therapy (PT) for hepatocellular carcinoma (HCC). Materials and methods Thirty-eight HCC lesions were studied retrospectively to assess changes in the dose distribution on two computed tomography (CT) scans. One was for treatment planning (1st-CT), and the other was for dose confirmation acquired during the course of PT (2nd-CT). The dose coverage of the clinical target volume (CTV-D98 ) and normal liver volume that received 30 Gy relative biological effectiveness (RBE) (liver-V30 ) were evaluated under each condition. Initial treatment planning on the 1st-CT was defined as reference, and three dose distributions recalculated using VM, DM, and MM on the 2nd-CT, were compared to it, respectively. In addition, the relationship between the CTV-D98 of each method and the distance between the center of mass (COM) of the CTV and the right diaphragm top was evaluated. Results For CTV-D98 , significant differences were observed between the reference and VM and DM, respectively (P = 0.013, P = 0.015). There were also significant differences between MM and VM and DM, respectively (P = 0.018, P = 0.036). Regarding liver-V30 , there was no significant difference in any of the methods, and there were no discernable difference due to the different setup methods. In DM, only two out of 34 cases with a distance from right diaphragm top to COM of CTV of 90 mm or less that CTV-D98 difference was 5% or more and CTV-D98 was worse than VM were confirmed. Conclusion Although MM is obviously the most effective method, it is suggested that DM may be particularly effective in cases where the distance from right diaphragm top to COM of CTV of 90 mm or less.

Background An individual dosimetry system is essential for the evaluation of precise doses in nuclear medicine. The purpose of this study was to develop a system for calculating not only absorbed doses but also EQDX(α/β) from the PET-CT images of patients for targeted alpha therapy (TAT), considering the dose dependence of the relative biological effectiveness, the dose-rate effect, and the dose heterogeneity. Methods A general-purpose Monte Carlo particle transport code PHITS was employed as the dose calculation engine in the system, while the microdosimetric kinetic model was used for converting the absorbed dose to EQDX(α/β). PHITS input files for describing the geometry and source distribution of a patient are automatically created from PET-CT images, using newly developed modules of the radiotherapy package based on PHITS (RT-PHITS). We examined the performance of the system by calculating several organ doses using the PET-CT images of four healthy volunteers after injecting 18F-NKO-035. Results The deposition energy map obtained from our system seems to be a blurred image of the corresponding PET data because annihilation γ-rays deposit their energies rather far from the source location. The calculated organ doses agree with the corresponding data obtained from OLINDA 2.0 within 20%, indicating the reliability of our developed system. Test calculations by replacing the labeled radionuclide from 18F to 211At suggest that large dose heterogeneity in a target volume is expected in TAT, resulting in a significant decrease of EQDX(α/β) for higher-activity injection. Conclusions As an extension of RT-PHITS, an individual dosimetry system for nuclear medicine was developed based on PHITS coupled with the microdosimetric kinetic model. It enables us to predict the therapeutic and side effects of TAT based on the clinical data largely available from conventional external radiotherapy.

Purpose Photon radiation therapy (x-ray radiation therapy [XRT] and gamma-ray radiation therapy [GRT]) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiation therapy (PRT) can preserve ovarian function when ovaries are positioned distal to the spread-out Bragg peak (SOBP) in tumors of the abdominopelvic region. This study compared anti-Mullerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival after in vivo mouse pelvic GRT versus PRT. Methods and Materials One hundred twenty-four female prepubertal mice received sham, GRT, or PRT with ovaries positioned at various depth with respect to the proton SOBP, with single doses of 1.8 or 0.2 Gy. AMH was measured at baseline, 1, 3, and 8 weeks after treatment, and the total number of surviving primordial follicles was counted. Multivariable linear mixed-effects modeling was used to assess the relationship between radiation therapy modality and dose on AMH and primordial follicle survival. Results For ovaries beyond the SOBP, ovarian function (P = .5) and ovarian primordial follicle (OPF; P = 1.0) were spared relative to sham controls. For ovaries in the SOBP plateau, ovarian function and primordial follicle reserve 8 weeks after treatment were reduced for all groups: 1.8 Gy GRT (βAMH = –4.9 ng/mL; βOPF = –728.2/animal), 1.8 Gy (relative biological effectiveness [RBE] = 1.1) PRT (βAMH = –5.1 ng/mL; βOPF = –728.2/animal), 0.2 Gy GRT (βAMH = –2.5 ng/mL; βOPF = –595.1/animal), and 0.2 Gy (RBE = 1.1) PRT (βAMH = –3.0 ng/mL; βOPF = –555.4/animal) relative to sham controls (all differences P Conclusions This study uses an animal model to demonstrate the safety of proton therapy in sparing fertility. Ovaries positioned beyond the SOBP during PRT maintain ovarian reserve, suggesting that a proton beam has no energy and exit dose beyond SOBP. This study proposes that proton therapy is much safer than photon radiation therapy to protect ovarian follicles with the same dose, and it supports further testing of proton therapy for abdominopelvic tumors in young women.

Purpose To investigate if radiographic imaging changes defined as necrosis correlate with regions in the brain with elevated linear energy transfer (LET) for proton radiation therapy treatments with partial brain involvement in central nervous system and patients with head and neck cancer. Methods and Materials Fifty patients with head and neck, skull base, or intracranial tumors who underwent proton therapy between 2004 to 2016 with a minimum prescription dose of 59.4 Gy (relative biological effectiveness) and with magnetic resonance imaging changes indicative of brain necrosis after radiation therapy were retrospectively reviewed. Each treatment plan was recalculated using Monte Carlo simulations to provide accurate dose distributions as well as 3-dimensional distributions of LET. To assess the effect of LET on radiographic imaging changes several voxel-based analyses were performed. Results In this patient cohort, LET adjusted for dose was not found to be associated with risk of brain necrosis. Conclusions A voxel-based analysis of brain necrosis as an endpoint is difficult owing to uncertainties in the origin of necrosis, timing of imaging, variability in patient specific radiosensitivity, and the simultaneous effect of dose and LET. Even though it is expected that the LET and thus relative biological effectiveness increases at the end of range, effects in patients might be small compared with interpatient variability of radiosensitivity and might be obscured by other confounding factors.

We used the method proposed by Schneider et al. Theor Biol Med Model 2011;8:27, to clarify how the radiation-induced secondary cancer incidence rate changes in patients after proton craniospinal irradiation (CSI) without and with vertebral-body-sparing (VBS). Eight patients aged 3–15 years who underwent proton CSI were enrolled in the study. For each case, two types of plan without and with VBS in the target were compared. The prescribed doses were assumed to be 23.4 Gy relative biological effectiveness (RBE) and 36 Gy (RBE). Using the dose–volume histograms of the two plans, the lifetime attributable risk (LAR) was calculated by both methods for each patient based on the dose data calculated using an XiO-M treatment planning system. Eight organs were analyzed as follows: lung, colon, stomach, small intestine, liver, bladder, thyroid and bone. When the prescribed dose used was 23.4 Gy (RBE), the average LAR differences and the average number needed to treat (NNT) between proton CSI without and with VBS were 4.04 and 24.8, respectively, whereas the average LAR difference and the average NNT were larger at 8.65 and 11.6, respectively, when the prescribed dose of 36 Gy (RBE) was used. The LAR for radiation-induced secondary cancer was significantly lower in proton CSI with VBS than without VBS in pediatric patients, especially for the colon, lung, stomach and thyroid. The results of this study could serve as reference data when considering how much of vertebral bodies should be included when performing proton CSI according to age in clinical settings.

Purpose The interruption time is the irradiation interruption that occurs at sites and operations such as the gantry, collimator, couch rotation, and patient setup within the field in radiotherapy. However, the radiobiological effect of prolonging the treatment time by the interruption time for tumor cells is little evaluated. We investigated the effect of the interruption time on the radiobiological effectiveness with photon beams based on a modified microdosimetric kinetic (mMK) model. Methods The dose‐mean lineal energy yD (keV/µm) of 6‐MV photon beams was calculated by the particle and heavy ion transport system (PHITS). We set the absorbed dose to 2 or 8 Gy, and the interruption time (τ) was set to 1, 3, 5, 10, 30, and 60 min. The biological parameters such as α0, β0, and DNA repair constant rate (a + c) values were acquired from a human non‐small‐cell lung cancer cell line (NCI‐H460) for the mMK model. We used two‐field and four‐field irradiation with a constant dose rate (3 Gy/min); the photon beams were paused for interruption time τ. We calculated the relative biological effectiveness (RBE) to evaluate the interruption time's effect compared with no interrupted as a reference. Results The yD of 6‐MV photon beams was 2.32 (keV/µm), and there was little effect by changing the water depth (standard deviation was 0.01). The RBE with four‐field irradiation for 8 Gy was decreased to 0.997, 0.975, 0.900, and 0.836 τ = 1, 10, 30, 60 min, respectively. In addition, the RBE was affected by the repair constant rate (a + c) value, the greater the decrease in RBE with the longer the interruption time when the (a + c) value was large. Conclusion The ~10‐min interruption of 6‐MV photon beams did not significantly impact the radiobiological effectiveness, since the RBE decrease was

The authors review the available data on damage to cortical neurons and incipient lenticular opacity in small laboratory animals after exposure to fast neutrons, accelerated multi-charged ions (AMCIs), and different doses of X- and γ-rays. Analysis and possible revision of maximum coefficients of relative biological effectiveness (RBEM) for these effects, as well as RBEM coefficients for other space radiation-induced impacts, including blast transformation, cytogenetic alterations, increased probability of tumor development in organs and tissues, and reduction in estimated life expectancy, will lay the grounds for reconsideration of the existing normative documents and calculations of generalized and equivalent doses for organs and tissues based on the absorbed dose values. At present, Russian GOST 25 645.218-90 “Space Crew Radiation Safety during Space Fight” and recommendations of the International Commission on Radiological Protection (ICRP, papers 60 and 61, 1994) reflect the dependence of space radiation quality factors (QFs) on linear energy transfer.

Purpose Tumor control probability (TCP)-based early regression index (ERITCP) is a radiobiological parameter that showed promising results in predicting pathologic complete response (pCR) on T2-weighted 1.5 T magnetic resonance (MR) images of patients with locally advanced rectal cancer. This study aims to validate the ERITCP in the context of low-tesla MR-guided radiation therapy, using images acquired with different magnetic field strength (0.35 T) and image contrast (T2/T1). Furthermore, the optimal timing for pCR prediction was estimated, calculating the ERI index at different biologically effective dose (BED) levels. Methods and Materials Fifty-two patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy were enrolled in this multi-institutional retrospective study. For each patient, a 0.35 T T2/T1-weighted MR image was acquired during simulation and on each treatment day. Gross tumor volume was contoured according to International Commission on Radiation Units Report 83 guidelines. According to the original definition, ERITCP was calculated considering the residual tumor volume at BED = 25 Gy. ERI was also calculated in correspondence with several BED levels: 13, 21, 32, 40, 46, 54, 59, and 67. The predictive performance of the different ERI indices were evaluated in terms of receiver operating characteristic curve. The robustness of ERITCP with respect to the interobserver variability was also evaluated considering 2 operators and calculating the intraclass correlation index. Results Fourteen patients showed pCR. ERITCP correctly 47 of 52 cases (accuracy = 90%), showing good results in terms of sensitivity (86%), specificity (92%), negative predictive value (95%), and positive predictive value (80%). The analysis at different BED levels shows that the best predictive performance is obtained when this parameter is calculated at BED = 25 Gy (area under the curve = 0.93). ERITCP results are robust with respect to interobserver variability (intraclass correlation index = 0.99). Conclusions This study confirmed the validity and the robustness of ERITCP as a pCR predictor in the context of low-tesla MR-guided radiation therapy and indicate 25 Gy as the best BED level to perform predictions.