Tissue Dose Research Articles

Радиологическая безопасность населения и персонала при двухкомпонентной ядерной энергетике

The Fundamentals of State Policy in the Field of Nuclear and Radiation Safety of the Russian Federation, approved by the President of the Russian Federation, indicate that the goal of state policy in this area is to ensure the protection of the population, considering modern requirements. The IAEA Fundamental Safety Principles emphasize the need to protect both current and future generations from radiation risks. The achievement of these safety goals is ensured by the development in Russia of new nuclear energy system based on a closed nuclear fuel cycle (CNFC) and fast neutron reactors (FNR). One of the objects of the new nuclear energy system is the Experimental Demonstration Energy Complex (EDEC) consisting of the BREST-OD-300 FNR, a reprocessing module and a fuel fabrication/refabrication module, located on the territory of JSC «SHK» in the Tomsk region. This article provides assessments of radiation carcinogenic risks for the population living in the 30-km zone of JSC «SHK» under normal operating conditions and for workers after potential emergency situations at EDEC facilities. The conditions for ensuring the protection of future generations of people are also justified. Radiation risk assessments are obtained directly from the dynamics of equivalent doses in human organs and tissues and modern risk models recommended by ICRP Publication 103. The predicted values of the risks of radiation carcinogenesis for the population and personnel are significantly lower than the current limits of NRB-99/2009 for both normal operation and potential exposure during accidents. It has been shown that transmutation of minor actinides during the development of CNFC based on FNR ensures the safety of future generations of people: it reduces the carcinogenic risk of americium by 213 times, neptunium by 101 times, and curium by 47 times. The effect of radiological equivalence of radioactive waste and natural uranium raw materials is achieved after 99 years of radioactive waste storage. Thus, the priority direction for the development of new nuclear power is the energy sector of the CNFC based on the FNR.

Dosimetric comparison of 6 MV and 10 MV flattening filter-free beams using small diameter cone for trigeminal neuralgia radiosurgery

Abstract Purpose: To compare the dosimetric characteristics and treatment delivery efficiency of trigeminal neuralgia (TN) stereotactic radiosurgery (SRS) patients previously treated with a 6 MV-FFF (flattening filter-free; radiation beam obtained by removing the flattening filter) beam versus those re-planned with a 10 MV-FFF beam using a conical collimator on the TrueBeam Novalis STx linear accelerator. Methods: Eleven patients with TN previously treated with a 6 MV-FFF beam following the SRS protocol of 90 Gy in a single fraction were selected. Plans were recalculated using 10 MV-FFF beam, maintaining the same dose prescription and beam angle configuration used with 6 MV-FFF beam. The dose gradient, volumes receiving 20 and 10 Gy, maximum dose and dose to 10% of the brainstem were recorded for both the energies. Efficiency was assessed by the average monitor unit (MU) and time per arc. The 10 MV-FFF machine was configured in the treatment planning system (TPS) to measure the tissue phantom ratio (TPR), dose profiles and scatter factors using RAZOR, PTW-60012 diodes and EBT3 radiochromic films. Results: Compared to the 6 MV-FFF, the 10 MV-FFF plans exhibit average increments in dose gradient, volume of 20 Gy and volume of 10 Gy of 3.8, 17.1 and 17.8%, respectively. Average increases of 6.5 and 18.1% were obtained for maximum dose and dose to 10% of the brainstem, respectively. An average increase of 31 MU/arc was observed for the 10 MV-FFF plans, with a 40% reduction in treatment time per arc. The TPR for the 10 MV-FFF beams increased by 10%, and a penumbra width of 0.3 mm was observed. Scatter factor increments of 15, 13.5, 12.7 and 10.3% were observed for the 6 MV-FFF over the 10 MV-FFF for cones of 4, 5, 6 and 7 mm, respectively. Conclusions: In TN SRS, the utilisation of 10 MV-FFF beams reduces treatment duration but results in an increased brainstem radiation dose. To mitigate this increase in brainstem dose, it is necessary to adjust the isocentre position.

Optimizing tumor treating fields for blood cancer therapy: Analysis of electric field distribution and dose density.

Blood cancer is a condition in which white blood cells grow uncontrollably. Tumor treating fields (TTF) are a modality of cancer treatment that utilizes electric fields to target malignant cells. To optimize the efficacy of TTF, it is necessary to investigate the distribution of electric field through varying electrode configurations and input parameters. This allows for enhancement of electric field intensity in targeted areas while minimizing intensity in sensitive areas. Analysis of electric field distribution was conducted through simulation of brachial models with varying electrode configurations and input parameters, utilizing the COMSOL Multiphysics 5.4 software. Additionally, investigations were carried out to assess tissue dose density. The dose density value at primary target for all electrode configurations and input parameters do not exceed the threshold value (770 W/m3), whereas the electric field value at the primary target satisfied the threshold value (100 V/m) on the system that used 4 plate-shaped electrodes and arm contour-shaped electrodes with an input voltage of 20 V, and at the input voltage 15 V, only 4 arm contour-shaped electrodes that satisfied the threshold value. An increase in input voltage, electrodes addition, and electrodes adjustment to skin contour shape result in an enhancement of electric field distribution and average electric field value at primary targets.

Histopathologically confirmed radiation-induced damage of the brain – an in-depth analysis of radiation parameters and spatio-temporal occurrence

BackgroundRadiation-induced damage (RID) after radiotherapy (RT) of primary brain tumors and metastases can be challenging to clinico-radiographically distinguish from tumor progression. RID includes pseudoprogression and radiation necrosis; the latter being irreversible and often associated with severe symptoms. While histopathology constitutes the diagnostic gold standard, biopsy-controlled clinical studies investigating RID remain limited. Whether certain brain areas are potentially more vulnerable to RID remains an area of active investigation. Here, we analyze histopathologically confirmed cases of RID in relation to the temporal and spatial dose distribution.MethodsHistopathologically confirmed cases of RID after photon-based RT for primary or secondary central nervous system malignancies were included. Demographic, clinical, and dosimetric data were collected from patient records and treatment planning systems. We calculated the equivalent dose in 2 Gy fractions (EQD22) and the biologically effective dose (BED2) for normal brain tissue (α/β ratio of 2 Gy) and analyzed the spatial and temporal distribution using frequency maps.ResultsThirty-three patients were identified. High-grade glioma patients (n = 18) mostly received one normofractionated RT series (median cumulative EQD22 60 Gy) to a large planning target volume (PTV) (median 203.9 ccm) before diagnosis of RID. Despite the low EQD22 and BED2, three patients with an accelerated hyperfractionated RT developed RID. In contrast, brain metastases patients (n = 15; 16 RID lesions) were often treated with two or more RT courses and with radiosurgery or fractionated stereotactic RT, resulting in a higher cumulative EQD22 (median 162.4 Gy), to a small PTV (median 6.7 ccm). All (n = 34) RID lesions occurred within the PTV of at least one of the preceding RT courses. RID in the high-grade glioma group showed a frontotemporal distribution pattern, whereas, in metastatic patients, RID was observed throughout the brain with highest density in the parietal lobe. The cumulative EQD22 was significantly lower in RID lesions that involved the subventricular zone (SVZ) than in lesions without SVZ involvement (median 60 Gy vs. 141 Gy, p = 0.01).ConclusionsAccelerated hyperfractionated RT can lead to RID despite computationally low EQD22 and BED2 in high-grade glioma patients. The anatomical location of RID corresponded to the general tumor distribution of gliomas and metastases. The SVZ might be a particularly vulnerable area.

A Prospective Study Assessing the Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Oligometastatic Bone Metastases

PurposeStereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone due to its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess the efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. Materials and MethodsIn this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at XXXX between December 2016 and May 2019. SBRT dose and fractionation regimen were not protocol-mandated. Local progression-free survival (LPFS), progression-free survival (PFS), prostatic specific antigen (PSA) progression, and overall survival (OS) were reported. Treatment-related toxicity was also reported. ResultsA total of 98 patients and 126 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (27.0%, 34/126), 30 Gy in 5 fractions (16.7%, 21/126), or 30/35 Gy in 5 fractions (16.7%, 21/126). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume (CTV) and higher dose to the gross tumor volume (GTV). Four patients (4.1%, 4/98) experienced local progression at one site for each patient (3.2%, 4/126). Among the entire cohort, 2-year LPFS (including death without local progression) was 84.8%, 2-year PFS (including deaths as well as local, distant, and PSA progression) was 47.5%, and 2-year OS was 87.3%. Twenty-six patients (26.5%, 26/98) developed treatment-related toxicities. ConclusionsOur study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

Red shell‐ high risk normal tissue in stereotactic radiosurgery

AbstractDue to the ablative nature of high prescription in Stereotactic Radiosurgery or stereotactic body radiation therapy (SRS/SBRT), the normal tissue surrounding the CTV receives the dose higher than tissue's dose constraint. A concept of Red Shell is proposed to define and quantify these tissue damaged in SBRT, using biological equivalent dose (BED) concept. The combination of biological factors and physics factors, including serial and parallel organ, dose gradient, dose distribution and fractionations, are further discussed to interpret the clinical meaning of Red Shell. This concept can also help planner to improve the optimization in planning process.

Nine years of plan of the day for cervical cancer: Plan library remains effective compared to fully online-adaptive techniques

Background and purposeSince 2011, our center has been using a library-based Plan-of-the-Day (PotD) strategy for external beam radiotherapy of cervical cancer patients to reduce normal tissue dose while maintaining adequate target coverage. With the advent of fully online-adaptive techniques such as daily online-adaptive replanning, further dose reduction may be possible. However, it is unknown how this reduction relates to plan library approaches, and how the most recent PotD strategies relate to no adaptation. In this study we compare the performance of our current PotD strategy with non-adaptive and fully online-adaptive techniques in terms of target volume size and normal tissue sparing. Materials and methodsTreatment data of 376 patients treated with the PotD protocol between June 2011 and April 2020 were included. The size of the Planning Target Volumes (PTVs) was reconstructed for different strategies: full online adaptation, no adaptation, and the latest clinical version of the PotD protocol. Normal tissue sparing was estimated by the difference in margin volume to construct the PTV and the volume overlap of the PTV with bladder and rectum. ResultsThe current version of our PotD approach reduced the PTV margin volume by a median of 250 cm3 compared to no adaptation. Bladder-PTV overlap decreased from a median of 142 to 71 cm3, and from 39 to 16 cm3 for rectum-PTV. Fully online-adaptive approaches could further decrease the PTV volume by 144 cm3 using a 5 mm margin for residual errors. In this scenario, bladder-PTV overlap was reduced to 35 cm3 and rectum-PTV overlap to 11 cm3. ConclusionThe current version of the PotD protocol is an effective technique to improve normal tissue sparing compared to no adaptation. Further sparing can be achieved using fully online-adaptive techniques, but at the cost of a more complex workflow and with a potentially limited impact. PotD-type protocols can therefore be considered as a suitable alternative to fully online-adaptive approaches.

Toward an improved assessment of dose conformity in radiotherapy.

Evaluation of dose conformity is important to ensure minimum dose to normal tissue and sufficient dose coverage of the planning target volume (PTV). The existing conformity indices depend on the PTV volume and do not differentiate between two different scenarios: overdosing normal tissue and underdosing PTV. In this study, we introduce a novel index to assess conformity of dose distributions in radiotherapy. The suggested conformity index is defined by the ratio of the volume representing actual "non-conformity" of the planned dose and the volume representing acceptable "non-conformity." The latter volume is produced by expanding the PTV. If both the average distance ( ) between the reference isodose surface and planning target volume and arbitrarily selected PTV expansion margin ( ) are much smaller than the size of the PTV, approximately equals the ratio . In this work, was utilized to analyze 90 cases of brain metastases treated with stereotactic radiation therapy (SRS) and 102 cases of lung cancer treated with stereotactic body radiation therapy (SBRT). For =0.1cm, all considered SRS treatment plans were characterized by while 2 out of 102 SBRT plans had . The average values of for SRS and SBRT plans were 0.31 and 0.43, respectively. For =0.2cm, all studied treatment plans had , and the average values of for SRS and SBRT plans were 0.15 and 0.25, respectively. The suggested conformity index varies less with PTV volume than the RTOG and Riet-Paddick indices frequently used for evaluation of dose conformity. In addition, can be expressed as a sum of two terms which describe "over-coverage" and "under-coverage" of the treatment target. The results confirm that can be used for evaluation of dose conformity in SRS and SBRT.

Monte Carlo simulations for targeted beta therapy: An optimization for liver lesions and comparison of dose distributions in other organs

ObjectiveTo optimize targeted beta therapy for liver lesions in adult male phantom by comparing the efficacy and safety profiles of five different beta-emitting radionuclides: 90Y, 166Ho, 153Sm, 47Sc, and 177Lu. MethodsThis study includes Monte Carlo simulations of the behavioral characteristics of five different beta emitters that have current or potential use in targeted beta therapy. The energy loss of beta particles moving within the material through ionization or chemical processes, the energy transferred to the material, the energy lost by beta particles along the distance traveled within the tissue, and consequently, the stopping power are calculated using the Bethe-Bloch formula. The CSDA (continuous slowing-down approximation) range of beta particles within the tissue is examined using ESTAR and GEANT codes, while the stopping power of the tissue is investigated using FLUKA, ESTAR, and GEANT codes. Tissue dose calculations for the target organ are obtained using the IDAC-Dose2.1 and MIRDcalc simulation programs, using parameters such as absorbed dose per accumulated activity (S-factor) and specific absorbed fraction (SAF). Additionally, dose and flux values are obtained using the PHITS program. ResultsThe behaviors and dose contribution of beta particles in liver tissue have been addressed in various ways. 90Y, which has the highest average beta energy, was observed to provide a higher absorbed dose value in the liver compared to other beta-emitting isotopes, while the lowest absorbed dose was observed with 177Lu. In other organs, it has been observed that 90Y and 47Sc contribute to a higher absorbed dose compared to other beta-emitting isotopes. ConclusionsThis study emphasizes the complexity and significance of targeted beta therapy optimization.

Advancing the Role of Proton Therapy for Spine Metastases Through Diagnostic Scan–Based Planning

PurposeMany patients with metastatic cancer live years beyond diagnosis, and there remains a need to improve the therapeutic ratio of metastasis-directed radiation for these patients. This study aimed to assess a process for delivering cost-effective palliative proton therapy to the spine using diagnostic scan–based planning (DSBP) and prefabricated treatment delivery devices. Materials and MethodsWe designed and characterized a reusable proton aperture system that adjusts to multiple lengths for spine treatment. Next, we retrospectively identified 10 patients scan treated with thoracic proton therapy who also had a diagnostic computed tomography within 4 months of simulation. We contoured a T6-T9 target volume on both the diagnostic scans (DS) and simulation scans (SS). Using the aperture system, we generated proton plans on the DS using a posterior–anterior beam with no custom range compensator to treat T6-T9 to 8 Gy × 1. Plans were transferred to the SS to compare coverage and normal tissue doses, followed by robustness analysis. Finally, we compared normal tissue doses and costs between proton and photon plans. Results were compared using the Wilcoxon signed-rank test. ResultsMedian D95% on the DS plans was 101% (range, 100%–102%) of the prescription dose. Median Dmax was 107% (range, 105%–108%). When transferred to SS, coverage and hot spots remained acceptable for all cases. Heart and esophagus doses did not vary between the DS and SS proton plans (P >.2). Robustness analysis with 5 mm X/Y/Z shifts showed acceptable coverage (D95% > 98%) for all cases. Compared with the proton plans, the mean heart dose was higher for both anterior–posterior/posterior–anterior and volumetric modulated arc therapy plans (P < .01). Cost for proton DSBP was comparable to more commonly used photon regimens. ConclusionProton DSBP is technically feasible and robust, with superior sparing of the heart compared with photons. Eliminating simulation and custom devices increases the value of this approach in carefully selected patients.

A Conceptual Design of a Novel Multi-Hexagonal Beta Applicator Intended to Treat Non-Melanoma Skin Cancers

Due to its short range in tissue and high dose gradient beta radiation may be used to the therapy of small and superficial skin lesions. In this short study a conceptual design of a novel multi-hexagonal beta applicator loaded with Yttrium-90 is presented. Calculations of dose rates around the applicator area performed using the beta-point source dose function formalism and initial results show that over 90\% of the beta radiation energy from the multi-hexagonal applicator loaded with Yttrium-90 is absorbed in the first layers of the skin tissue. Results show that the multi-hexagonal beta applicator has the potential to be used in the brachytherapy treatment of non-melanoma skin cancers.

The dirty and clean dose concept: Towards creating proton therapy treatment plans with a photon-like dose response.

Applying tolerance doses for organs at risk (OAR) from photon therapy introduces uncertainties in proton therapy when assuming a constant relative biological effectiveness (RBE) of 1.1. This work introduces the novel dirty and clean dose concept, which allows for creating treatment plans with a more photon-like dose response for OAR and, thus, less uncertainties when applying photon-based tolerance doses. The concept divides the 1.1-weighted dose distribution into two parts: the clean and the dirty dose. The clean and dirty dose are deposited by protons with a linear energy transfer (LET) below and above a set LET threshold, respectively. For the former, a photon-like dose response is assumed, while for the latter, the RBE might exceed 1.1. To reduce the dirty dose in OAR, a MaxDirtyDose objective was added in treatment plan optimization. It requires setting two parameters: LET threshold and max dirty dose level. A simple geometry consisting of one target volume and one OAR in water was used to study the reduction in dirty dose in the OAR depending on the choice of the two MaxDirtyDose objective parameters during plan optimization. The best performing parameter combinations were used to create multiple dirty dose optimized (DDopt) treatment plans for two cranial patient cases. For each DDopt plan, 1.1-weighted dose, variable RBE-weighted dose using the Wedenberg RBE model and dose-average LETd distributions as well as resulting normal tissue complication probability (NTCP) values were calculated and compared to the reference plan (RefPlan) without MaxDirtyDose objectives. In the water phantom studies, LET thresholds between 1.5 and 2.5keV/µm yielded the best plans and were subsequently used. For the patient cases, nearly all DDopt plans led to a reduced Wedenberg dose in critical OAR. This reduction resulted from an LET reduction and translated into an NTCP reduction of up to 19 percentage points compared to the RefPlan. The 1.1-weighted dose in the OARs was slightly increased (patient 1: 0.45Gy(RBE), patient 2: 0.08Gy(RBE)), but never exceeded clinical tolerance doses. Additionally, slightly increased 1.1-weighted dose in healthy brain tissue was observed (patient 1: 0.81Gy(RBE), patient 2: 0.53Gy(RBE)). The variation of NTCP values due to variation of α/β from 2 to 3Gy was much smaller for DDopt (2 percentage points (pp)) than for RefPlans (5 pp). The novel dirty and clean dose concept allows for creating biologically more robust proton treatment plans with a more photon-like dose response. The reduced uncertainties in RBE can, therefore, mitigate uncertainties introduced by using photon-based tolerance doses for OAR.

Development of a framework for risk assessment of dietary carcinogens.

Although there are a number of guidance documents and frameworks for evaluation of carcinogenicity, none of the current methods fully reflects the state of the science. Common limitations include the absence of dose-response assessment and not considering the impact of differing exposure patterns (e.g., intermittent, high peaks vs. lower, continuous exposures). To address these issues, we have developed a framework for risk assessment of dietary carcinogens. This framework includes an enhanced approach for weight of evidence (WOE) evaluation for genetic toxicology data, with a focus on evaluating studies based on the most recent testing guidance to determine whether a chemical is a mutagen. Included alongside our framework is a discussion of resources for evaluating tissue dose and the temporal pattern of internal dose, taking into account the chemical's toxicokinetics. The framework then integrates the mode of action (MOA) and associated dose metric category with the exposure data to identify the appropriate approach(es) to low-dose extrapolation and level of concern associated with the exposure scenario. This framework provides risk managers with additional flexibility in risk management and risk communication options, beyond the binary choice of linear low-dose extrapolation vs. application of uncertainty factors.

Clinical Insight on Proton Therapy for Paediatric Rhabdomyosarcoma.

This paper offers an insight into the use of Proton Beam Therapy (PBT) in paediatric patients with rhabdomyosarcoma (RMS). This paper provides a comprehensive analysis of the literature, investigating comparative photon-proton dosimetry, outcome, and toxicity. In the complex and multimodal scenario of the treatment of RMS, clear evidence of the therapeutic superiority of PBT compared to other modern photon techniques has not yet been demonstrated; however, PBT can be considered an excellent treatment option, in particular for young children and patients with specific primary sites, such as the head and neck area (and especially the parameningeal regions), genito-urinary, pelvic, and paravertebral regions. The unique depth-dose characteristics of protons can be exploited to achieve significant reductions in normal tissue doses and may allow an escalation of tumour doses and greater sparing of normal tissues, thus potentially improving local control while at the same time reducing toxicity and improving quality of life. However, access of children with RMS (and more in general with solid tumors) to PBT remains a challenge, due to the limited number of available proton therapy installations.

Evaluation of kV Triggered Fiducial Tracking for Prostate SBRT Intrafraction Motion Management.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment for localized prostate cancer. Given the high dose per fraction, a high degree of precision is needed during SBRT treatment delivery. Fiducial marker tracking is a means of monitoring intrafraction motion, ensuring precise treatment delivery and potentially allowing for decreased planning target volume (PTV) margins. We present a 5-year single institution experience to characterize the performance of fiducial tracking. We analyzed 132 consecutive patients treated at our institution with prostate SBRT between July 2017 and November 2022 using fiducial tracking with the TrueBeam Auto Beam Hold feature. Patients were treated using a 5-fraction dose escalation protocol, with many receiving a simultaneous integrated boost to the GTV up to 45 Gy. All patients underwent pre-treatment cone-beam CT and planar kV imaging with rigid registration to the fiducial markers. Cine kV images were acquired every 3-5 seconds during treatment delivery and the beam was paused when a fiducial deviated from a given 4 mm diameter tolerance region. Additional intrafraction 2D or 3D imaging techniques were then used to realign the fiducials. Data was retrieved from the record and verify system including: number and type of intrafraction images, number of treatment interruptions, number of and magnitude of shifts, and total treatment time. The average number of cine kV images acquired per fraction and for the total 5 fraction SBRT course were 86.6 ± 26.8 and 425.6 ± 136.8 respectively. Assuming 1.3 mGy/kV image, the fiducial tracking process delivered an average additional 55.3 cGy over the full treatment course. On average, the beam was paused 5.0 ± 2.5 times per fraction (range 1-21 interruptions) and shifts were applied 4.1 ± 2.1 times (range 0-10.2 times) per fraction. Over the 2560 total shifts applied for all the patients, the average(max) translations were 0.6 (12) mm vrt, 0.7 (22) mm lng, and 0.9 (5) mm lat and the average(max) rotations were 0.19 (5.9)° pitch, 0.01 (2.4)° roll, and 0.16 (6.4)° rtn. Overall, 2.4% of shifts were greater than the 4 mm PTV margin and 4.2% of vertical shifts were greater than the 2.5 mm posterior margin. Average fraction treatment time was 27 ± 9.7 minutes. Fiducial tracking affords the potential to increase daily treatment precision when delivering prostate SBRT. Our data indicate that the beam is typically paused several times during a prostate SBRT fraction, with occasional large shifts required, suggesting the importance of intrafraction motion management. Downsides of kV triggered fiducial tracking include extension of treatment times and delivery of additional radiation dose to the patient. We are investigating if this method of motion management might allow for a reduction in PTV margins to reduce normal tissue dosing.

A Prospective Study Assessing the Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Oligometastatic Bone Metastases

Stereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone due to its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. In this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at one of two academic institutions between December 2016 and May 2019. Local progression-free survival (LPFS), progression-free survival (PFS), prostatic specific antigen (PSA) progression, and overall survival (OS) were reported. Treatment-related toxicity was also reported. A total of 98 patients and 131 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled in the study was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (26.0%, 34/131), 30 Gy in 5 fractions (19.1%, 25/131), or 30/35 Gy in 5 fractions (16.0%, 21/131). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume (CTV) and higher dose to the gross tumor volume (GTV). Four patients (4.1%, 4/98) experienced local progression at one site for each patient (3.1%, 4/131). Among patients who progressed locally, the median time to local recurrence was 25.8 months (31.0 months among prostate cancer patients, N = 2, and 14.5 months among non-prostate cancer patients, N = 2). Among the entire cohort, 2-year LPFS (including death without local progression) was 85.0%, 2-year PFS (including deaths as well as local, distant, and PSA-based progression) was 47.0%, and 2-year OS was 87.5%. Twenty-seven patients (27.6%, 27/98) developed treatment-related toxicities, and most were Grade 1 (19.4%, 19/98) and 2 (4.1%, 4/98). Four patients (4.1%, 4/98) developed Grade 3 toxicities; there were no Grade 4 toxicities. The most common toxicity was fatigue (10.2%, 10/98). Of 68 treated spine metastases, there were four (5.9%, 4/68) vertebral fractures. Among these four patients, median time to fracture was 23.5 months (range 14.2-39.2 months). Our study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

Superiority of BNCT Treatment Planning Metrics Achieved Using Novel vs. Reference (BPA-F) Pharmaceuticals in Head and Neck Locations

Several novel boron delivery compounds currently under investigation by our group have demonstrated formulation, biodistribution, and dose response benefits in small animal models [1]. In this study we analyze the potential clinical impact of these compounds for boron neutron capture therapy (BNCT) in human patients. Pharmacokinetic models were used to estimate the tumor and normal tissue boron concentrations after continuous infusion of the novel compounds and BPA-F. Patient model segmentation, material assignment, and alignment of one or more treatment beams were exported from a commercial treatment planning system (TPS) to a novel dose calculation tool. This information was used to generate a voxelized model that incorporated the source, beam shaping assembly, collimator, and patient materials so that the full albedo effect was included in each dose calculation. Physical dose from 10B(n,α), 14N(n,p), 1H(n,n') interactions plus gamma rays from 1H(n,γ) and other reactions within the patient and treatment equipment were calculated by Monte Carlo transport of particles originating in a pre-generated phase space at the cover surface. RBE and CBE weighting factors are applied to combine these four physical dose volumes into an equivalent dose volume, and these five dose volumes were passed back to the TPS for evaluation. Tumor dose was increased by up to 2.6x for the novel compounds while normal tissue doses were constant or slightly reduced in comparison to BPA-F plans. Alternatively, for identical tumor dose the normal tissue doses and treatment time were reduced by up to 2.6x. In addition, in some cases it was possible to generate a single beam treatment plan using the new compounds that delivered higher tumor dose and lower normal tissues doses than a multiple beam plan using BPA-F. This study demonstrates both dosimetric and practical benefits of the new compounds in comparison to BPA-F, including the potential to deliver treatment using fewer beam directions and correspondingly easier treatment setups and higher patient throughput. The potential of these compounds to extend the range of clinical indications for BNCT is also discussed. These results motivate upcoming experimental testing of the key assumptions involved in their calculation.

Adaptive Radiotherapy with Dose Fractionation Painting

Efficacy of dose fractionation is dependent on tumor radiosensitivity. However, due to intra-tumoral dose response heterogeneity, the advantage of fractionation cannot be fully utilized. FDG-PET/CT has been used to assess intra-tumoral dose response during the treatment course. Thus, radiosensitivity of different sub-volumes within the individual tumors can be assessed and used to design dose fractionation. For each patient, the pre-treatment FDG-PET/CT and a feedback FDG-PET/CT obtained within the 3rd week of the chemo-radiotherapy for HN cancer were used to construct tumor voxel dose response matrix, DRM. Biologically equivalent dose EQD2 was determined using the DRM and assuming relative stability of the radiation double-hit effect, meanwhile normal tissue EQD2 was determined assuming the corresponding α/β = 3.0. Tumor voxel EQD2 ratio was calculated with a given limitation of normal tissue EQD2 and used to determine tumor voxel fractionation (Table). Tumor was divided into few sub-volumes based on ranges of the tumor voxel DRM value. Different fractionation doses, but same number of fractions, were selected to ensure that the planning dose distribution can be simultaneously delivered. Table shows the EQD2 of tumor voxel DRM for each given fractionation and normal tissue dose limitation. The treatment dose efficiency increases exponentially as increasing dose per fraction for those of resistant tumor voxels, i.e., DRM > = 0.7. The 2 Gy per fraction was used within the first 3 treatment weeks before tumor voxel dose response assessed. After the 15 fractions, tumor voxel dose fractionation will be adjusted with respect to its DRM and the expected treatment dose. Typically, 3 sub-volumes for each resistant tumor were segmented and designed with 3 fractionation regimens. With respect to normal tissue EQD2 constraint < = 70 Gy, the corresponding EQD2 was 55 ∼ 73 Gy for tumor sub-volume with DRM = 0.1 ∼ 0.6; 77 ∼ 90 Gy for tumor sub-volume with DRM = 0.65 ∼ 0.75; > 101 Gy for tumor sub-volume with DRM > = 0.8 respectively. For very resistant tumor cells i.e., DRM > 0.9, the EQD2 > 160 Gy can be achieved or > 244 Gy if the normal tissue EQD2 constraint can be relaxed to 90 Gy for the small resistant tumor sub-volume. For the study patients, tumor sub-volume with DRM > 0.9 = 0.128 ∼ 7.4cc. Adaptive dose fractionation painting can be achieved followed by the dose response assessment. Dependent on the size and location of resistant tumor sub-volumes, tumor EQD2 could be largely improved without increasing normal tissue dose.

A New Treatment Planning Method for Efficient Proton ARC Therapy with Direct Minimization of Number of Energy Jumps

The optimization of energy layer distributions is crucial for efficient proton ARC therapy: on one hand, a sufficient number of energy layers is needed to ensure the plan quality; on the other hand, an excess number of energy jumps can substantially slow down the treatment delivery. This work will develop a new treatment plan optimization method with direct minimization of number of energy jumps (NEJ), which will be shown to outperform state-of-the-art methods in both plan quality and delivery efficiency. The proposed method jointly optimizes the plan quality and minimizes the NEJ. To minimize NEJ, (1) the proton spots x is summed per energy layer to form the energy vector y; (2) y is binarized via sigmoid transform into y1; (3) y1 is multiplied with a predefined energy order vector via dot product into y2; (4) y2 is filtered through the finite-differencing kernel into y3 in order to identify NEJ; (5) only the NEJ of y3 is penalized, while x is optimized for plan quality. The solution algorithm to this new method is based on iterative convex relaxation. The new method is validated in comparison with state-of-the-art methods called energy sequencing (ES) method and energy matrix (EM) method. In terms of delivery efficiency, the new method had fewer NEJ, less energy switching time, and generally less total delivery time. In terms of plan quality, the new method had smaller optimization objective values, lower normal tissue dose, and generally better target coverage. A head-and-neck case is provided in the table with the following dosimetric parameters: planning objective value F; conformity index CI; homogeneity index HI; mean dose of larynx DOAR; mean body dose Dbody; the unit of dose is Gy. We have developed a new treatment plan optimization method with direct minimization of NEJ, and demonstrated that this new method outperformed state-of-the-art methods (ES and EM) in both plan quality and delivery efficiency.

Dose Constraints and Planning Considerations for Thoracic Radiation Therapy: Delphi Consensus from a National Survey of Experts

Many physicians refer to trial protocols or published guidelines (NCCN, QUANTEC, HyTEC) for dose-volume histogram (DVH) metrics. However, there may be variation in implementing these metrics during plan optimization. Some studies have suggested better outcomes for patients treated at high-volume, high-expertise centers. These differences may in part be due to greater standardization or center-specific treatment planning processes. We surveyed radiation oncologists with stated thoracic-specific expertise using the Delphi method to formulate consensus DVH metrics that would be considered ideal for high-quality radiation treatment plans. Thoracic radiation oncology experts were identified using departmental websites of ACGME-accredited radiation oncology programs. After confirming their expertise, panelists were invited to submit their institutional templates and complete three rounds of questions related to normal organ dose constraints, target coverage metrics, prescribing practices, and other planning considerations. Queried radiation schemes included conventional fractionation, twice-daily fractionation, and stereotactic body radiation therapy (3 and 5 fractions). Preliminary consensus statements were generated using median values for DVH metrics and were iteratively refined in subsequent surveys. Consensus was pre-defined as ≥75% agreement among panelists. A total of 194 experts were invited, and 100 agreed to participate. The panel was 28% female and included experts from 29 states with a median of 11 years of clinical experience (IQR 6-19). 89% specialized in 1-2 disease sites. Response rates for the Demographics, round 1, 2, and 3 surveys were 83%, 78%, 57%, and 55%, respectively. 93% of panelists believed that DVH metrics should provide thresholds for both optimal and acceptable criteria for treatment planning. 49 of the 96 proposed normal tissue dose constraint statements were iterated to consensus (Table 1), and 5 of 7 proposed target coverage metric statements achieved consensus. This study highlights the heterogeneity in metrics used by thoracic radiation oncologists and provides levels of consensus on ideal and acceptable dose constraints as guidance for treatment planning. Future directions include using these statements to develop prescription templates and acceptance criteria for treatment planning systems for widespread use as well as extending this Delphi approach to additional disease sites.