The Peaks and Valleys of Photon Versus Proton Spatially Fractionated Radiotherapy.

Spatially-fractionated radiotherapy (SFRT) delivers high doses to small areas of tumor while sparing adjacent tissue, including intervening disease. In this review, we explore the evolution of SFRT technological advances, contrasting approaches with photon and proton beam radiotherapy. We discuss unique dosimetric considerations and physical properties of SFRT, as well as review the preclinical literature that provides an emerging understanding of biological mechanisms. We emphasize crucial areas of future study and highlight clinical trials that are underway to assess SFRT's safety and efficacy, with a focus on immunotherapeutic synergies. The review concludes with practical considerations for SFRT's clinical application, advocating for strategies that leverage its unique dosimetric and biological properties for improved patient outcomes.

The Story Behind the First Mini-BEAM Photon Radiation Treatment: What is the Mini-Beam and Why is it Such an Advance?

Radiation treatment has been the cornerstone in cancer management. However, long term treatment-related morbidity always accompanies tumor control which has significant impact on quality of life of the patient who has survived the cancer. Spatially fractionated radiation has the potential to achieve both cure and to avoid dreaded long term sequelae. The first ever randomized study of mini-beam radiation treatment (MBRT) of canine brain tumor has clearly shown the ability to achieve this goal. Dogs have gyrencephalic brains functionally akin to human brain. We here report long term follow-up and final outcome of the dogs, revealing both tumor control and side effects on normal brain. The results augur potential for conducting human studies with MBRT.

A comprehensive Study of the Out of Field Non Target Dose Associated with 6 and 10 MV Flattened and Flattening Filter Free X Ray Beam in a True Beam Linear Accelerator.

AIM: To evaluate the out-of-field dose associated with flattened (FF) and flattening filter-free (FFF) 6 and 10 MV X-ray beams in a TrueBeam linear accelerator (Linac). MATERIALS AND METHODS: Measurements were taken in a slab phantom using the metal oxide semiconductor field effect transistor (MOSFET) detector at varying depths (dmax, 5 cm, and 10 cm) for clinically relevant field sizes and up to 30 cm from the field edges for 6 and 10 MV FF and FFF beams in TrueBeam Linac. Dose calculation accuracy of the analytic anisotropic algorithm (AAA) and Acuros algorithm was investigated in the out-of-field region. Similarly, the out-of-field dose associated with volumetric modulated arc therapy (VMAT) head-and-neck plan delivered to a body phantom was evaluated. RESULTS: The out-of-field dose for both FF and FFF photon beams (6 and 10 MV) decreased with increasing distance from the field boundary and size. Furthermore, regardless of FF in the field, higher-energy photon beams were associated with lower out-of-field dose. Both algorithms underestimated the dose in the out-of-field region, with AAA failing to calculate the out-of-field dose at 15 cm from the field edge and Acuros failing to calculate out-of-field radiation at 20 cm. At 5 cm from the field edge, an average of 50% underestimation was observed, and at 10 cm, an average of 60% underestimation was observed for both FF and FFF (6 and 10 MV) beams. The VMAT head-and-neck plan performed with the FFF beam resulted in a lower out-of-field dose than the FF beam for a comparable dose distribution. CONCLUSION: Compared with flattened beams, the FFF modes on TrueBeam Linac exhibited a clinically relevant reduction in the out-of-field dose. Further dosimetric studies are warranted to determine the significant benefit of FFF beams across different cancer sites.

Biological optimization for hybrid proton-photon radiotherapy.

Objective.Hybrid proton-photon radiotherapy (RT) is a cancer treatment option to broaden access to proton RT. Additionally, with a refined treatment planning method, hybrid RT has the potential to offer superior plan quality compared to proton-only or photon-only RT, particularly in terms of target coverage and sparing organs-at-risk (OARs), when considering robustness to setup and range uncertainties. However, there is a concern regarding the underestimation of the biological effect of protons on OARs, especially those in close proximity to targets. This study seeks to develop a hybrid treatment planning method with biological dose optimization, suitable for clinical implementation on existing proton and photon machines, with each photon or proton treatment fraction delivering a uniform target dose.Approach.The proposed hybrid biological dose optimization method optimized proton and photon plan variables, along with the number of fractions for each modality, minimizing biological dose to the OARs and surrounding normal tissues. To mitigate underestimation of hot biological dose spots, proton biological dose was minimized within a ring structure surrounding the target. Hybrid plans were designed to be deliverable separately and robustly on existing proton and photon machines, with enforced uniform target dose constraints for the proton and photon fraction doses. A probabilistic formulation was utilized for robust optimization of setup and range uncertainties for protons and photons. The nonconvex optimization problem, arising from minimum monitor unit constraint and dose-volume histogram constraints, was solved using an iterative convex relaxation method.Main results.Hybrid planning with biological dose optimization effectively eliminated hot spots of biological dose, particularly in normal tissues surrounding the target, outperforming proton-only planning. It also provided superior overall plan quality and OAR sparing compared to proton-only or photon-only planning strategies.Significance.This study presents a novel hybrid biological treatment planning method capable of generating plans with reduced biological hot spots, superior plan quality to proton-only or photon-only plans, and clinical deliverability on existing proton and photon machines, separately and robustly.

Proton versus photon adjuvant radiotherapy: a multicenter comparative evaluation of recurrence following spinal chordoma resection.

OBJECTIVE: Chordomas are rare tumors of the skull base and spine believed to arise from the vestiges of the embryonic notochord. These tumors are locally aggressive and frequently recur following resection and adjuvant radiotherapy. Proton therapy has been introduced as a tissue-sparing option because of the higher level of precision that proton-beam techniques offer compared with traditional photon radiotherapy. This study aimed to compare recurrence in patients with chordomas receiving proton versus photon radiotherapy following resection by applying tree-based machine learning models. METHODS: The clinical records of all patients treated with resection followed by adjuvant proton or photon radiotherapy for chordoma at Mayo Clinic were reviewed. Patient demographics, type of surgery and radiotherapy, tumor recurrence, and other variables were extracted. Decision tree classifiers were trained and tested to predict long-term recurrence based on unseen data using an 80/20 split. RESULTS: Fifty-three patients with a mean ± SD age of 55.2 ± 13.4 years receiving surgery and adjuvant proton or photon therapy to treat chordoma were identified; most patients were male. Gross-total resection was achieved in 54.7% of cases. Proton therapy was the most common adjuvant radiotherapy (84.9%), followed by conventional or external-beam radiation therapy (9.4%) and stereotactic radiosurgery (5.7%). Patients receiving proton therapy exhibited a 40% likelihood of having recurrence, significantly lower than the 88% likelihood observed in those treated with nonproton therapy. This was confirmed on logistic regression analysis adjusted for extent of tumor resection and tumor location, which revealed that proton adjuvant radiotherapy was associated with a decreased risk of recurrence (OR 0.1, 95% CI 0.01-0.71; p = 0.047) compared with photon therapy. The decision tree algorithm predicted recurrence with an accuracy of 90% (95% CI 55.5%-99.8%), with the lowest risk of recurrence observed in patients receiving gross-total resection with adjuvant proton therapy (23%). CONCLUSIONS: Following resection, adjuvant proton therapy was associated with a lower risk of chordoma recurrence compared with photon therapy. The described machine learning models were able to predict tumor progression based on the extent of tumor resection and adjuvant radiotherapy modality used.

[Research Photon Energy Spectrum of Medical Linear Accelerator by Monte Carlo Method].

Objective: The distribution of the photon energy spectrum in isocenter plane of the medical linear accelerator and the influence of secondary collimator on the photon energy spectrum are studied. Methods Use the BEAMnrc program to simulate the transmission of the 6 MeV electrons and photons in 5 cm×5 cm,10 cm×10 cm,15 cm×15 cm and 20 cm×20 cm fields in treatment head of the medical linear accelerator, where a phase space file was set up at the isocenter plane to record the particle information passing through this plane. The BEAMdp program is used to analyze the phase space file, in order to obtain the distribution of the photon energy spectrum in isocenter plane and the influence of secondary collimator on the photon energy spectrum. Results: By analyzing the photon energy spectrum of a medical linear accelerator with a nominal energy of 6 MV, it is found that the secondary collimator has little effect on the photon energy spectrum; different fields have different photon energy spectrum distributions; the photon energy spectrum in different central regions of the same field have the same normalized distribution. Conclusion: In the dose calculation of radiation therapy, the influence of photon energy spectrum should be carefully considered.

Photon vs proton hypofractionation in prostate cancer: A systematic review and meta-analysis.

BACKGROUND: High-level evidence on hypofractionated proton therapy (PT) for localized and locally advanced prostate cancer (PCa) patients is currently missing. The aim of this study is to provide a systematic literature review to compare the toxicity and effectiveness of curative radiotherapy with photon therapy (XRT) or PT in PCa. METHODS: PubMed, Embase, and the Cochrane Library databases were systematically searched up to April 2022. Men with a diagnosis of PCa who underwent curative hypofractionated RT treatment (PT or XRT) were included. Risk of grade (G) ≥ 2 acute and late genitourinary (GU) OR gastrointestinal (GI) toxicity were the primary outcomes of interest. Secondary outcomes were five-year biochemical relapse-free survival (b-RFS), clinical relapse-free, distant metastasis-free, and prostate cancer-specific survival. Heterogeneity between study-specific estimates was assessed using Chi-square statistics and measured with the I2 index (heterogeneity measure across studies). RESULTS: A total of 230 studies matched inclusion criteria and, due to overlapped populations, 160 were included in the present analysis. Significant lower rates of G ≥ 2 acute GI incidence (2 % vs 7 %) and improved 5-year biochemical relapse-free survival (95 % vs 91 %) were observed in the PT arm compared to XRT. PT benefits in 5-year biochemical relapse-free survival were maintained for the moderate hypofractionated arm (p-value 0.0122) and among patients in intermediate and low-risk classes (p-values < 0.0001 and 0.0368, respectively). No statistically relevant differences were found for the other considered outcomes. CONCLUSION: The present study supports that PT is safe and effective for localized PCa treatment, however, more data from RCTs are needed to draw solid evidence in this setting and further effort must be made to identify the patient subgroups that could benefit the most from PT.

TOPAS simulation of photoneutrons in radiotherapy: accuracy and speed with variance reduction.

Objective. We provide optimal particle split numbers for speeding up TOPAS Monte Carlo simulations of linear accelerator (linac) treatment heads while maintaining accuracy. In addition, we provide a new TOPAS physics module for simulating photoneutron production and transport.Approach.TOPAS simulation of a Siemens Oncor linac was used to determine the optimal number of splits for directional bremsstrahlung splitting as a function of the field size for 6 MV and 18 MV x-ray beams. The linac simulation was validated against published data of lateral dose profiles and percentage depth-dose curves (PDD) for the largest square field (40 cm side). In separate simulations, neutron particle split and the custom TOPAS physics module was used to generate and transport photoneutrons, called 'TsPhotoNeutron'. Verification of accuracy was performed by comparing simulations with published measurements of: (1) neutron yields as a function of beam energy for thick targets of Al, Cu, Ta, W, Pb and concrete; and (2) photoneutron energy spectrum at 40 cm laterally from the isocenter of the Oncor linac from an 18 MV beam with closed jaws and MLC.Main results.The optimal number of splits obtained for directional bremsstrahlung splitting enhanced the computational efficiency by two orders of magnitude. The efficiency decreased with increasing beam energy and field size. Calculated lateral profiles in the central region agreed within 1 mm/2% from measured data, PDD curves within 1 mm/1%. For the TOPAS physics module, at a split number of 146, the efficiency of computing photoneutron yields was enhanced by a factor of 27.6, whereas it improved the accuracy over existing Geant4 physics modules.Significance.This work provides simulation parameters and a new TOPAS physics module to improve the efficiency and accuracy of TOPAS simulations that involve photonuclear processes occurring in high-Zmaterials found in linac components, patient devices, and treatment rooms, as well as to explore new therapeutic modalities such as very-high energy electron therapy.

Updated Analysis of Comparative Toxicity of Proton and Photon Radiation for Prostate Cancer.

PURPOSE: Previous comparative effectiveness studies have not demonstrated a benefit of proton beam therapy (PBT) compared with intensity-modulated radiation therapy (IMRT) for prostate cancer. An updated comparison of GI and genitourinary (GU) toxicity is needed. METHODS: We investigated the SEER-Medicare linked database, identifying patients with localized prostate cancer diagnosed from 2010 to 2017. Procedure and diagnosis codes indicative of treatment-related toxicity were identified. As a sensitivity analysis, we also identified toxicity based only on procedure codes. Patients who underwent IMRT and PBT were matched 2:1 on the basis of clinical and sociodemographic characteristics. We then compared GI and GU toxicity at 6, 12, and 24 months after treatment. RESULTS: The final sample included 772 PBT patients matched to 1,544 IMRT patients. The frequency of GI toxicity for IMRT versus PBT was 3.5% versus 2.5% at 6 months (P = .18), 9.5% versus 10.2% at 12 months (P = .18), and 20.5% versus 23.4% at 24 months (P = .11). The frequency of only procedure codes indicative of GI toxicity for IMRT versus PBT was too low to be reported and not significantly different. The frequency of GU toxicity for IMRT versus PBT was 6.8% versus 5.7% (P = .30), 14.3% versus 12.2% (P = .13), and 28.2% versus 25.8% (P = .21) at 6, 12, and 24 months, respectively. When looking only at procedure codes, the frequency of GU toxicity for IMRT was 1.0% at 6 months, whereas it was too infrequent to report for PBT (P = .64). GU toxicity for IMRT versus PBT was 3.3% versus 2.1% (P = .10), and 8.7% versus 6.7% (P = .10) at 12 and 24 months, respectively. CONCLUSION: In this observational study, there were no statistically significant differences between PBT and IMRT in terms of GI or GU toxicity.

FLASH Radiotherapy: What Can FLASH's Ultra High Dose Rate Offer to the Treatment of Patients With Sarcoma?

FLASH is an emerging treatment paradigm in radiotherapy (RT) that utilizes ultra-high dose rates (UHDR; >40 Gy)/s) of radiation delivery. Developing advances in technology support the delivery of UHDR using electron and proton systems, as well as some ion beam units (eg, carbon ions), while methods to achieve UHDR with photons are under investigation. The major advantage of FLASH RT is its ability to increase the therapeutic index for RT by shifting the dose response curve for normal tissue toxicity to higher doses. Numerous preclinical studies have been conducted to date on FLASH RT for murine sarcomas, alongside the investigation of its effects on relevant normal tissues of skin, muscle, and bone. The tumor control achieved by FLASH RT of sarcoma models is indistinguishable from that attained by treatment with standard RT to the same total dose. FLASH's high dose rates are able to mitigate the severity or incidence of RT side effects on normal tissues as evaluated by endpoints ranging from functional sparing to histological damage. Large animal studies and clinical trials of canine patients show evidence of skin sparing by FLASH vs. standard RT, but also caution against delivery of high single doses with FLASH that exceed those safely applied with standard RT. Also, a human clinical trial has shown that FLASH RT can be delivered safely to bone metastasis. Thus, data to date support continued investigations of clinical translation of FLASH RT for the treatment of patients with sarcoma. Toward this purpose, hypofractionated irradiation schemes are being investigated for FLASH effects on sarcoma and relevant normal tissues.

Modeling hypoxia-induced radiation resistance and the impact of radiation sources.

Hypoxia contributes significantly to resistance in radiotherapy. Our research rigorously examines the influence of microvascular morphology on radiotherapy outcome, specifically focusing on how microvasculature shapes hypoxia within the microenvironment and affects resistance to a standard treatment regimen (30×2GyRBE). Our computational modeling extends to the effects of different radiation sources. For photons and protons, our analysis establishes a clear correlation between hypoxic volume distribution and treatment effectiveness, with vascular density and regularity playing a crucial role in treatment success. On the contrary, carbon ions exhibit distinct effectiveness, even in areas of intense hypoxia and poor vascularization. This finding points to the potential of carbon-based hadron therapy in overcoming hypoxia-induced resistance to RT. Considering that the spatial scale analyzed in this study is closely aligned with that of imaging data voxels, we also address the implications of these findings in a clinical context envisioning the possibility of detecting subvoxel hypoxia.

SAPPHIRE -establishment of small animal proton and photon image-guided radiation experiments.

Thein vivoevolution of radiotherapy necessitates innovative platforms for preclinical investigation, bridging the gap between bench research and clinical applications. Understanding the nuances of radiation response, specifically tailored to proton and photon therapies, is critical for optimizing treatment outcomes. Within this context, preclinicalin vivoexperimental setups incorporating image guidance for both photon and proton therapies are pivotal, enabling the translation of findings from small animal models to clinical settings. TheSAPPHIREproject represents a milestone in this pursuit, presenting the installation of the small animal radiation therapy integrated beamline (SmART+ IB, Precision X-Ray Inc., Madison, Connecticut, USA) designed for preclinical image-guided proton and photon therapy experiments at University Proton Therapy Dresden. Through Monte Carlo simulations, low-dose on-site cone beam computed tomography imaging and quality assurance alignment protocols, the project ensures the safe and precise application of radiation, crucial for replicating clinical scenarios in small animal models. The creation of Hounsfield lookup tables and comprehensive proton and photon beam characterizations within this system enable accurate dose calculations, allowing for targeted and controlled comparison experiments. By integrating these capabilities,SAPPHIREbridges preclinical investigations and potential clinical applications, offering a platform for translational radiobiology research and cancer therapy advancements.

Brainstem toxicity after proton or photon therapy in children and young adults with localized intracranial ependymoma: A French retrospective study.

BACKGROUND AND PURPOSE: Ependymoma is the third most frequent childhood braintumor. Standard treatment is surgery followed by radiation therapy including proton therapy (PBT). Retrospective studies have reported higher rates of brainstem injury after PBT than after photon therapy (XRT). We report a national multicenter study of the incidence of brainstem injury after XRT versus PBT, and their correlations with dosimetric data. MATERIAL AND METHODS: We included all patients aged < 25 years who were treated with PBT or XRT for intracranial ependymoma at five French pediatric oncology reference centers between 2007 and 2020. We reviewed pre-irradiation MRI, follow-up MRIs over the 12 months post-treatment and clinical data. RESULTS: Of the 83 patients, 42 were treated with PBT, 37 with XRT, and 4 with both (median dose: 59.4 Gy, range: 53­60). No new or progressive symptomatic brainstem injury was found. Four patients presented asymptomatic radiographic changes (punctiform brainstem enhancement and FLAIR hypersignal), with median onset at 3.5 months (range: 3.0­9.4) after radiation therapy, and median offset at 7.6 months (range: 3.7­7.9). Two had been treated with PBT, one with XRT, and one with mixed XRT-PBT. Prescribed doses were 59.4, 55.8, 59.4 and 54 Gy. CONCLUSION: Asymptomatic radiographic changes occurred in 4.8% of patients with ependymoma in a large national series. There was no correlation with dose or technique. No symptomatic brainstem injury was identified.

Beam quality and the mystery behind the lower percentage depth dose in grid radiation therapy.

Grid therapy recently has been picking momentum due to favorable outcomes in bulky tumors. This is being termed as Spatially Fractionated Radiation Therapy (SFRT) and lattice therapy. SFRT can be performed with specially designed blocks made with brass or cerrobend with repeated holes or using multi-leaf collimators where dosimetry is uncertain. The dosimetric challenge in grid therapy is the mystery behind the lower percentage depth dose (PDD) in grid fields. The knowledge about the beam quality, indexed by TPR20/10 (Tissue Phantom Ratio), is also necessary for absolute dosimetry of grid fields. Since the grid may change the quality of the primary photons, a new [Formula: see text] should be evaluated for absolute dosimetry of grid fields. A Monte Carlo (MC) approach is provided to resolving the dosimetric issues. Using 6 MV beam from a linear accelerator, MC simulation was performed using MCNPX code. Additionally, a commercial grid therapy device was used to simulate the grid fields. Beam parameters were validated with MC model for output factor, depth of maximum dose, PDDs, dose profiles, and TPR20/10. The electron and photon spectra were also compared between open and grid fields. The dmax is the same for open and grid fields. The PDD with grid is lower (~ 10%) than the open field. The difference in TPR20/10 of open and grid fields is observable (~ 5%). Accordingly, TPR20/10 is still a good index for the beam quality in grid fields and consequently choose the correct [Formula: see text] in measurements. The output factors for grid fields are 0.2 lower compared to open fields. The lower depth dose with grid therapy is due to lower depth fluence with scatter radiation but it does not impact the dosimetry as the calibration parameters are insensitive to the effective beam energies. Thus, standard dosimetry in open beam based on international protocol could be used.

A triple-imaging-modality system for simultaneous measurements of prompt gamma photons, prompt x-rays, and induced positrons during proton beam irradiation.

Objective. Prompt gamma photon, prompt x-ray, and induced positron imaging are possible methods for observing a proton beam's shape from outside the subject. However, since these three types of images have not been measured simultaneously nor compared using the same subject, their advantages and disadvantages remain unknown for imaging beam shapes in therapy. To clarify these points, we developed a triple-imaging-modality system to simultaneously measure prompt gamma photons, prompt x-rays, and induced positrons during proton beam irradiation to a phantom.Approach. The developed triple-imaging-modality system consists of a gamma camera, an x-ray camera, and a dual-head positron emission tomography (PET) system. During 80 MeV proton beam irradiation to a polymethyl methacrylate (PMMA) phantom, imaging of prompt gamma photons was conducted by the developed gamma camera from one side of the phantom. Imaging of prompt x-rays was conducted by the developed x-ray camera from the other side. Induced positrons were measured by the developed dual-head PET system set on the upper and lower sides of the phantom.Main results. With the proposed triple-imaging-modality system, we could simultaneously image the prompt gamma photons and prompt x-rays during proton beam irradiation. Induced positron distributions could be measured after the irradiation by the PET system and the gamma camera. Among these imaging modalities, image quality was the best for the induced positrons measured by PET. The estimated ranges were actually similar to those imaged with prompt gamma photons, prompt x-rays and induced positrons measured by PET.Significance. The developed triple-imaging-modality system made possible to simultaneously measure the three different beam images. The system will contribute to increasing the data available for imaging in therapy and will contribute to better estimating the shapes or ranges of proton beam.

Determination of thePrpand radial dose correction factor in reference dosimetry.

Objectives.In an addendum to AAPM TG-51 protocol, McEwenet al, (DOI:10.1118/1.4866223) introduced a new factorPrpto account for the radial dose distribution of the photon beam over the detector volume mainly in flattening filter free (FFF) beams.Prpand its extension to non-FFF beam reference dosimetry is investigated to see its impact in a clinical situation.Approches.ThePrpwas measured using simplified version of Sudhyadhomet al(DOI:10.1118/1.4941691) for Elekta and Varian FFF beams with two commonly used calibration detectors; PTW-30013 and Exradin-A12 ion chambers after acquiring high resolution profiles in detectors cardinal coordinates. For radial dose correction factor, the ion chambers were placed in a small water phantom and the central axis position was set to center of the sensitive volume on the treatment table and was studied by rotating the table by 15-degree interval from -90 to +90 degrees with respect to the initial (zero) position.Main results.The magnitude ofPrpvaries very little with machine, detector and beam energies to a value of 1.003 ± 0.0005 and 1.005 ± 0.0005 for 6FFF and 10FFF, respectively. The radial anisotropy for the Elekta machine with Exradin-A12 and PTW-30013 detector the magnitudes are in the range of (0.9995±0.0011 to 1.0015±0.0010) and (0.9998±0.0007 to 1.0015±0.0010), respectively. Similarly, for the Varian machine with Exradin-A12 and PTW-30013 ion chambers, the magnitudes are in the range of (1.0004±0.0010 to 1.0018±0.0018) and (1.0006±0.0009 to 1.0027±0.0007), respectively.Significance.ThePrpis ≤ 0.3% and 0.5% for 6FFF and 10FFF, respectively. The radial dose correction factor in regular beams also does not impact the dosimetry where the maximum magnitude is ±0.2% which is within experimental uncertainty.

Carbon Ion and Photon Radiation Therapy Show Enhanced Antitumoral Therapeutic Efficacy With Neoantigen RNA-LPX Vaccines in Preclinical Colon Carcinoma Models.

PURPOSE: Personalized liposome-formulated mRNA vaccines (RNA-LPX) are a powerful new tool in cancer immunotherapy. In preclinical tumor models, RNA-LPX vaccines are known to achieve potent results when combined with conventional X-ray radiation therapy (XRT). Densely ionizing radiation used in carbon ion radiation therapy (CIRT) may induce distinct effects in combination with immunotherapy compared with sparsely ionizing X-rays. METHODS AND MATERIALS: Within this study, we investigate the potential of CIRT and isoeffective doses of XRT to mediate tumor growth inhibition and survival in murine colon adenocarcinoma models in conjunction with neoantigen (neoAg)-specific RNA-LPX vaccines encoding both major histocompatibility complex (MHC) class I- and class II-restricted tumor-specific neoantigens. We characterize tumor immune infiltrates and antigen-specific T cell responses by flow cytometry and interferon-γ enzyme-linked immunosorbent spot (ELISpot) analyses, respectively. RESULTS: NeoAg RNA-LPX vaccines significantly potentiate radiation therapy-mediated tumor growth inhibition. CIRT and XRT alone marginally prime neoAg-specific T cell responses detected in the tumors but not in the blood or spleens of mice. Infiltration and cytotoxicity of neoAg-specific T cells is strongly driven by RNA-LPX vaccines and is accompanied by reduced expression of the inhibitory markers PD-1 and Tim-3 on these cells. The neoAg RNA-LPX vaccine shows similar overall therapeutic efficacy in combination with both CIRT and XRT, even if the physical radiation dose is lower for carbon ions than for X-rays. CONCLUSIONS: We hence conclude that the combination of CIRT and neoAg RNA-LPX vaccines is a promising strategy for the treatment of radioresistant tumors.

Inverse planning of lung radiotherapy with photon and proton beams using a discrete ordinates Boltzmann solver.

Objective. A discrete ordinates Boltzmann solver has recently been developed for use as a fast and accurate dose engine for calculation of photon and proton beams. The purpose of this study is to apply the algorithm to the inverse planning process for photons and protons and to evaluate the impact that this has on the quality of the final solution.Approach.The method was implemented into an iterative least-squares inverse planning optimiser, with the Boltzmann solver used every 20 iterations over the total of 100 iterations. Elemental dose distributions for the intensity modulation and the dose changes at the intermediate iterations were calculated by a convolution algorithm for photons and a simple analytical model for protons. The method was evaluated for 12 patients in the heterogeneous tissue environment encountered in radiotherapy of lung tumours. Photon arc and proton arc treatments were considered in this study. The results were compared with those for use of the Boltzmann solver solely at the end of inverse planning or not at all.Main results.Application of the Boltzmann solver at the end of inverse planning shows the dose heterogeneity in the planning target volume to be greater than calculated by convolution and empirical methods, with the median root-mean-square dose deviation increasing from 3.7 to 5.3 for photons and from 1.9 to 3.4 for proton arcs. Use of discrete ordinates throughout inverse planning enables homogeneity of target coverage to be maintained throughout, the median root-mean-square dose deviation being 3.6 for photons and 2.3 for protons. Dose to critical structures is similar with discrete ordinates and conventional methods. Time for inverse planning with discrete ordinates takes around 1-2 h using a contemporary computing environment.Significance.By incorporating the Boltzmann solver into an iterative least squares inverse planning optimiser, accurate dose calculation in a heterogeneous medium is obtained throughout inverse planning, with the result that the final dose distribution is of the highest quality.

Combinatorial approach of immuno-proton therapy in cancer: Rationale and potential impact.

Cancer management is an expansive, growing, and evolving field. In the last decade or so, immunotherapy (IT) and particle beam therapy have made a tremendous impact in this domain. IT has already established itself as the fourth pillar of oncology. Recent emphasis has been centred around combination therapy, postulating additive or multiplicative effects of combining IT with one or more of the three conventional "pillars," that is, surgery, chemotherapy, and radiotherapy. Radio-IT is being increasingly explored and has shown promising outcomes in both preclinical and clinical settings. Particle beam therapy such as protons, when used as the radiotherapeutic modality in conjunction with IT, can potentially limit toxicities and improve this synergism further. Modern proton therapy has demonstrated a reduction in integral dose of radiation and radiation-induced lymphopenia in various sites. Protons, by virtue of their inherent clinically desirable physical and biological characteristics, namely, high linear energy transfer, relative biological effectiveness of range 1.1-1.6, and proven anti-metastatic and immunogenic potential in preclinical studies, might have a superior immunogenic profile than photons. Proton-IT combination is being studied currently by various groups in lung , head neck and brain tumors, and should be evaluated further in other subsites to replicate preclinical outcomes in a clinical setting. In this review, we summarize the currently available evidence for combinatorial approaches and feasibility of proton and IT combination, and thereafter highlight the emerging challenges for practical application of the same in clinics, while also proposing plausible solutions.