Very high-energy electron therapy as light-particle alternative to transmission proton FLASH therapy - An evaluation of dosimetric performances.

PURPOSE: Clinical translation of FLASH-radiotherapy (RT) to deep-seated tumours is still a technological challenge. One proposed solution consists of using ultra-high dose rate transmission proton (TP) beams of about 200-250 MeV to irradiate the tumour with the flat entrance of the proton depth-dose profile. This work evaluates the dosimetric performance of very high-energy electron (VHEE)-based RT (50-250 MeV) as a potential alternative to TP-based RT for the clinical transfer of the FLASH effect. METHODS: Basic physics characteristics of VHEE and TP beams were compared utilizing Monte Carlo simulations in water. A VHEE-enabled research treatment planning system was used to evaluate the plan quality achievable with VHEE beams of different energies, compared to 250 MeV TP beams for a glioblastoma, an oesophagus, and a prostate cancer case. RESULTS: Like TP, VHEE above 100 MeV can treat targets with roughly flat (within ± 20 %) depth-dose distributions. The achievable dosimetric target conformity and adjacent organs-at-risk (OAR) sparing is consequently driven for both modalities by their lateral beam penumbrae. Electron beams of 400[500] MeV match the penumbra of 200[250] MeV TP beams and penumbra is increased for lower electron energies. For the investigated patient cases, VHEE plans with energies of 150 MeV and above achieved a dosimetric plan quality comparable to that of 250 MeV TP plans. For the glioblastoma and the oesophagus case, although having a decreased conformity, even 100 MeV VHEE plans provided a similar target coverage and OAR sparing compared to TP. CONCLUSIONS: VHEE-based FLASH-RT using sufficiently high beam energies may provide a lighter-particle alternative to TP-based FLASH-RT with comparable dosimetric plan quality.

Deterioration of Visual Acuity after Brachytherapy and Proton Therapy of Uveal Melanoma, and Methods of Counteracting This Complication Based on Recent Publications.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The eyeball is the most common extracutaneous location of melanoma. UM is a huge threat to a patient's life. It metastasizes distantly via blood vessels, but it can also spread locally and infiltrate extraocular structures. The treatment uses surgical methods, which include, among others, enucleation and conservative methods, such as brachytherapy (BT), proton therapy (PT), stereotactic radiotherapy (SRT), stereotactic radiosurgery (SRS), transpupillary thermotherapy (TTT) and photodynamic therapy. The key advantage of radiotherapy, which is currently used in most patients, is the preservation of the eyeball with the risk of metastasis and mortality comparable to that of enucleation. Unfortunately, radiotherapy very often leads to a significant deterioration in visual acuity (VA) as a result of radiation complications. This article is a review of the latest research on ruthenium-106 (Ru-106) brachytherapy, iodine-125 (I-125) brachytherapy and proton therapy of uveal melanoma that took into account the deterioration of eye function after therapy, and also the latest studies presenting the new concepts of modifications to the applied treatments in order to reduce radiation complications and maintain better visual acuity in treated patients.

Biophysical characterization of collimated and uncollimated fields in pencil beam scanning proton therapy.

Objective. The lateral dose fall-off in proton pencil beam scanning (PBS) technique remains the preferred choice for sparing adjacent organs at risk as opposed to the distal edge due to the proton range uncertainties and potentially high relative biological effectiveness. However, because of the substantial spot size along with the scattering in the air and in the patient, the lateral penumbra in PBS can be degraded. Combining PBS with an aperture can result in a sharper dose fall-off, particularly for shallow targets.Approach. The aim of this work was to characterize the radiation fields produced by collimated and uncollimated 100 and 140 MeV proton beams, using Monte Carlo simulations and measurements with a MiniPIX-Timepix detector. The dose and the linear energy transfer (LET) were then coupled with publishedin silicobiophysical models to elucidate the potential biological effects of collimated and uncollimated fields.Main results. Combining an aperture with PBS reduced the absorbed dose in the lateral fall-off and out-of-field by 60%. However, the results also showed that the absolute frequency-averaged LET (LETF) values increased by a maximum of 3.5 keVµm-1in collimated relative to uncollimated fields, while the dose-averaged LET (LETD) increased by a maximum of 7 keVµm-1. Despite the higher LET values produced by collimated fields, the predicted DNA damage yields remained lower, owing to the large dose reduction.Significance. This work demonstrated the dosimetric advantages of combining an aperture with PBS coupled with lower DNA damage induction. A methodology for calculating dose in water derived from measurements with a silicon-based detector was also presented. This work is the first to demonstrate experimentally the increase in LET caused by combining PBS with aperture, and to assess the potential DNA damage which is the initial step in the cascade of events leading to the majority of radiation-induced biological effects.

Out-of-field measurements and simulations of a proton pencil beam in a wide range of dose rates using a Timepix3 detector: Dose rate, flux and LET.

Stray radiation produced by ultra-high dose-rates (UHDR) proton pencil beams is characterized using ASIC-chip semiconductor pixel detectors. A proton pencil beam with an energy of 220 MeV was utilized to deliver dose rates (DR) ranging from conventional radiotherapy DRs up to 270 Gy/s. A MiniPIX Timepix3 detector equipped with a silicon sensor and integrated readout electronics was used. The chip-sensor assembly and chipboard on water-equivalent backing were detached and immersed in the water-phantom. The deposited energy, particle flux, DR, and the linear energy transfer (LET(Si)) spectra were measured in the silicon sensor at different positions both laterally, at different depths, and behind the Bragg peak. At low-intensity beams, the detector is operated in the event-by-event data-driven mode for high-resolution spectral tracking of individual particles. This technique provides precise energy loss response and LET(Si) spectra with radiation field composition resolving power. At higher beam intensities a rescaling of LET(Si) can be performed as the distribution of the LET(Si) spectra exhibits the same characteristics regardless of the delivered DR. The integrated deposited energy and the absorbed dose can be thus measured in a wide range. A linear response of measured absorbed dose was obtained by gradually increasing the delivered DR to reach UHDR beams. Particle tracking of scattered radiation in data-driven mode could be performed at DRs up to 0.27 Gy/s. In integrated mode, the saturation limits were not reached at the measured out-of-field locations up to the delivered DR of over 270 Gy/s. A good agreement was found between measured and simulated absorbed doses.

Impact of beam-hardening corrections on proton relative stopping power estimates from single- and dual-energy CT.

A major contributing factor to proton range uncertainty is the conversion of computed tomography (CT) Hounsfield units (HU) to proton relative stopping power (RSP). This uncertainty is heightened in the presence of X-ray beam-hardening artifact (BHA), which has two manifestations: cupping and streaking, especially in and near bone tissue. This uncertainty can affect the accuracy of proton RSP calculation for treatment planning in proton radiotherapy. Dual-energy CT (DECT) and iterative beam-hardening correction (iBHC) both show promise in mitigating CT BHA. This present work attempts to analyze the relative robustness of iBHC and DECT techniques on both manifestations of BHA. The stoichiometric method for HU to RSP conversion was used for single-energy CT (SECT) and DECT-based monochromatic techniques using a tissue substitute phantom. Cupping BHA was simulated by measuring the HU of a bone substitute plug in wax/3D-printed phantoms of increasing size. Streaking BHA was simulated by placing a solid water plug between two bone plugs in a wax phantom. Finally, the effect of varying calibration phantom size on RSP was calculated in an anthropomorphic head phantom. The RSP decreased -0.002 cm-1 as phantom size increased for SECT but remained largely constant when iBHC applied or with DECT techniques. The RSP varied a maximum of 2.60% in the presence of streaking BHA in SECT but was reduced to 1.40% with iBHC. For DECT techniques, the maximum difference was 2.40%, reduced to 0.6% with iBHC. Comparing calibration phantoms of 20- and 33-cm diameter, maximum voxel differences of 5 mm in the water-equivalent thickness were observed in the skull but reduced to 1.3 mm with iBHC. The DECT techniques excelled in mitigating cupping BHA, but streaking BHA still could be observed. The use of iBHC reduced RSP variation with BHA in both SECT and DECT techniques.

Electrophysiological and Pathological Impact of Medium-Dose External Carbon Ion and Proton Beam Radiation on the Left Ventricle in an Animal Model.

Background Medium-dose (25 gray) x-ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x-ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium-dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3-month or 6-month follow-up, the animals underwent an open-chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium-dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

Proton Therapy for Localized Prostate Cancer: Long-Term Results From a Single-Center Experience.

PURPOSE: Although proton therapy is controversial, it has been used to treat localized prostate cancer over the past 2 decades. The purpose of this study is to examine the long-term efficacy and toxicity of proton therapy for localized prostate cancer. METHODS AND MATERIALS: This was a retrospective observational study of 2021 patients from 2003 to 2014 at a single institution. Patients were classified using the risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019. Ninety-eight percent of the patients received 74 Gy (relative biological effectiveness) in 37 fractions. Fifty-one and 6% of the patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The outcomes were the time of freedom from biochemical relapse and the time to late toxicity by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The outcomes were estimated using the Kaplan-Meier method and were analyzed using multivariable Cox proportional hazards models. RESULTS: The median follow-up period was 84 months (interquartile range, 60-110). The 5- and 10-year freedom from biochemical relapse rates were 100% and 100%, 99% and 88%, 93% and 86%, 90% and 79%, 88% and 68%, and 76% and 63% for the very low, low, favorable intermediate, unfavorable intermediate, high, and very high-risk groups, respectively. Patients with higher risk experienced biochemical relapse after shorter periods. The 5-year rates of grade 2 or higher late genitourinary and gastrointestinal toxicity were 2.2% and 4.0%, respectively. The results of multivariable analyses indicate that younger patients more often experienced biochemical relapse. CONCLUSIONS: This study demonstrates the favorable biochemical controls of proton therapy even in advanced localized prostate cancer patients with a low incidence of late toxicities, supporting the feasibility of conducting prospective clinical trials. The risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019, are useful to classify patients with localized prostate cancer. Our findings might suggest the necessity to develop a treatment strategy that accounts for the patient's age.

Evaluation of the activation of brass apertures in proton therapy using gamma-ray spectrometry and Monte Carlo simulations.

Collimating apertures are used in proton therapy to laterally conform treatment fields to the target volume. While this is a standard technique in passive spreading treatment heads, patient-specific apertures can supplement pencil-beam scanning (PBS) techniques to sharpen the lateral dose fall-off. A radiation protection issue is that proton-induced nuclear reactions can lead to the formation of radionuclides in the apertures. In the experiments of the current study, cylindrical, thick brass targets were irradiated with quasi-monoenergetic proton fields of 100.0 MeV and of 226.7 MeV in PBS mode. The radioactivation of these two brass samples was characterised with a low-level gamma-ray spectrometer. The activation products were scored in a Monte Carlo simulation, too, and compared with the experimental activities. For the high-energy field, 63Zn, 60Cu, and 61Cu were the most important short-lived isotopes regarding the measured specific activity. After irradiation with the 100.0 MeV field, 62Cu, 63Zn, and 60Cu had the highest activity. Regarding long-lived isotopes, which determine the storage time of the used apertures, the isotopes 57Co, 65Zn, 54Mn, 56Co had the largest contribution to the activity. The relative difference of activities between simulation and experiment was typically between 10%-20% for short-lived nuclides and were up to a factor of five larger for long-lived nuclides. Summarising experiments and simulations for both incident proton energies, 62Cu was the most important detected residual nucleus regardless if specific activity or equivalent dose is considered.

Early results and volumetric analysis after spot-scanning proton therapy with concomitant hyperthermia in large inoperable sacral chordomas.

OBJECTIVE: Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS:: Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS:: Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION: Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE:: This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.

In vitro biological response of cancer and normal tissue cells to proton irradiation not affected by an added magnetic field.

To optimize beam delivery and conformality of proton therapy, MRI integration has been proposed. Therefore, we investigated if proton irradiation in a magnetic field would change biological responses. Our data in cancer cell lines and stem cell-derived organoid models suggest that a magnetic field does not modify the biological response.

Highly efficient and sensitive patient-specific quality assurance for spot-scanned proton therapy.

The purpose of this work was to develop an end-to-end patient-specific quality assurance (QA) technique for spot-scanned proton therapy that is more sensitive and efficient than traditional approaches. The patient-specific methodology relies on independently verifying the accuracy of the delivered proton fluence and the dose calculation in the heterogeneous patient volume. A Monte Carlo dose calculation engine, which was developed in-house, recalculates a planned dose distribution on the patient CT data set to verify the dose distribution represented by the treatment planning system. The plan is then delivered in a pre-treatment setting and logs of spot position and dose monitors, which are integrated into the treatment nozzle, are recorded. A computational routine compares the delivery log to the DICOM spot map used by the Monte Carlo calculation to ensure that the delivered parameters at the machine match the calculated plan. Measurements of dose planes using independent detector arrays, which historically are the standard approach to patient-specific QA, are not performed for every patient. The nozzle-integrated detectors are rigorously validated using independent detectors in regular QA intervals. The measured data are compared to the expected delivery patterns. The dose monitor reading deviations are reported in a histogram, while the spot position discrepancies are plotted vs. spot number to facilitate independent analysis of both random and systematic deviations. Action thresholds are linked to accuracy of the commissioned delivery system. Even when plan delivery is acceptable, the Monte Carlo second check system has identified dose calculation issues which would not have been illuminated using traditional, phantom-based measurement techniques. The efficiency and sensitivity of our patient-specific QA program has been improved by implementing a procedure which independently verifies patient dose calculation accuracy and plan delivery fidelity. Such an approach to QA requires holistic integration and maintenance of patient-specific and patient-independent QA.

Addition of luminescence process in Monte Carlo simulation to precisely estimate the light emitted from water during proton and carbon-ion irradiation.

Although luminescence of water lower in energy than the Cerenkov-light threshold during proton and carbon-ion irradiation has been found, the phenomenon has not yet been implemented for Monte Carlo simulations. The results provided by the simulations lead to misunderstandings of the physical phenomenon in optical imaging of water during proton and carbon-ion irradiation. To solve the problems, as well as to clarify the light production of the luminescence of water, we modified a Monte Carlo simulation code to include the light production from the luminescence of water and compared them with the experimental results of luminescence imaging of water. We used GEANT4 for the simulation of emitted light from water during proton and carbon-ion irradiation. We used the light production from the luminescence of water using the scintillation process in GEANT4 while those of Cerenkov light from the secondary electrons and prompt gamma photons in water were also included in the simulation. The modified simulation results showed similar depth profiles to those of the measured data for both proton and carbon-ion. When the light production of 0.1 photons/MeV was used for the luminescence of water in the simulation, the simulated depth profiles showed the best match to those of the measured results for both the proton and carbon-ion compared with those used for smaller and larger numbers of photons/MeV. We could successively obtain the simulated depth profiles that were basically the same as the experimental data by using GEANT4 when we assumed the light production by the luminescence of water. Our results confirmed that the inclusion of the luminescence of water in Monte Carlo simulation is indispensable to calculate the precise light distribution in water during irradiation of proton and carbon-ion.

Long-term outcomes in patients treated with proton therapy for localized prostate cancer.

The aim of this retrospective study was to report long-term clinical outcomes in patients treated with proton therapy (PT) for localized prostate cancer. Between 2001 and 2014, 1375 consecutive patients were treated with PT. Patients were classified into prognostic risk groups based on the National Comprehensive Cancer Network criteria. Freedom from biochemical relapse (FFBR), cancer-specific survival (CSS) and incidence of late gastrointestinal (GI)/genitourinary (GU) toxicities were calculated. Multivariate analysis was performed to identify clinical prognostic factors for FFBR and late toxicities. The median follow-up period was 70 months (range, 4-145 months). In total, 99% of patients received 74 Gy (relative biologic effectiveness [RBE]); 56% of patients received neoadjuvant androgen deprivation therapy. For the low-, intermediate-, high-, and very high-risk groups, 5-year FFBR was 99% (95% confidence intervals [CI], 96-100%), 91% (95% CI, 88-93%), 86% (95% CI, 82-89%), and 66% (95% CI, 53-76%), respectively, and 5-year CSS was 100% (95% CI, 100-100%), 100% (95% CI, 100-100%) , 99% (95% CI, 97-100%), and 95% (95% CI, 94-98%), respectively. Patient age, T classification, Gleason score, prostate-specific antigen, and percentage of positive cores were significant prognostic factors for FFBR. Grade 2 or higher GI and GU toxicities were 3.9% and 2.0%. Patient age was a prognostic factor for both late GI and GU toxicities. This study represents the largest cohort of patients treated with PT for localized prostate cancer, with the longest follow-up to date. Our results demonstrate that the biochemical control of PT is favorable particularly for high- and very high-risk patients with lower late genitourinary toxicity and indicates the necessity of considering patient age in the treatment protocols.

Current Standard and Future Perspectives in Non-Surgical Therapy for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive liver tumor with a poor 5-year survival rate. Many HCCs are not amenable to surgical resection, because of tumor size, location, or because of the patient's poor liver function, a common obstacle to HCC therapy, because HCCs almost always develop in chronically inflamed livers. SUMMARY: In recent years, many efforts have been made to improve patient survival by conducting clinical trials investigating local and systemic treatment options for patients with unresectable tumors. These treatment options include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), selective internal radiotherapy with yttrium-90 (SIRT), stereotactic body radiation therapy (SBRT), proton beam therapy, molecular targeted therapy, and checkpoint inhibition. In this "to-the-point" article, we review the current standard and summarize the most recent findings in unresectable HCC treatment. KEY POINTS: (1) RFA is currently the preferred treatment for patients with tumor burden restricted to the liver and not eligible for surgical resection; (2) TACE is utilized in patients who are not eligible for RFA because of tumor location and/or number of tumor lesions; (3) SIRT might improve treatment responses achieved by TACE and is feasible in patients with portal vein thrombosis; (4) new radiation therapy treatment modalities such as SBRT and proton beam therapy show promising results for local tumor control; and (5) sorafenib remains the first-line systemic treatment option after several large clinical trials have failed to show superiority of other molecular targeted therapies in HCC patients.

From prompt gamma distribution to dose: a novel approach combining an evolutionary algorithm and filtering based on Gaussian-powerlaw convolutions.

Range verification and dose monitoring in proton therapy is considered as highly desirable. Different methods have been developed worldwide, like particle therapy positron emission tomography (PT-PET) and prompt gamma imaging (PGI). In general, these methods allow for a verification of the proton range. However, quantification of the dose from these measurements remains challenging. For the first time, we present an approach for estimating the dose from prompt γ-ray emission profiles. It combines a filtering procedure based on Gaussian-powerlaw convolution with an evolutionary algorithm. By means of convolving depth dose profiles with an appropriate filter kernel, prompt γ-ray depth profiles are obtained. In order to reverse this step, the evolutionary algorithm is applied. The feasibility of this approach is demonstrated for a spread-out Bragg-peak in a water target.

Can We Advance Proton Therapy for Prostate? Considering Alternative Beam Angles and Relative Biological Effectiveness Variations When Comparing Against Intensity Modulated Radiation Therapy.

PURPOSE: For prostate treatments, robust evidence regarding the superiority of either intensity modulated radiation therapy (IMRT) or proton therapy is currently lacking. In this study we investigated the circumstances under which proton therapy should be expected to outperform IMRT, particularly the proton beam orientations and relative biological effectiveness (RBE) assumptions. METHODS AND MATERIALS: For 8 patients, 4 treatment planning strategies were considered: (A) IMRT; (B) passively scattered standard bilateral (SB) proton beams; (C) passively scattered anterior oblique (AO) proton beams, and (D) AO intensity modulated proton therapy (IMPT). For modalities (B)-(D) the dose and linear energy transfer (LET) distributions were simulated using the TOPAS Monte Carlo platform and RBE was calculated according to 3 different models. RESULTS: Assuming a fixed RBE of 1.1, our implementation of IMRT outperformed SB proton therapy across most normal tissue metrics. For the scattered AO proton plans, application of the variable RBE models resulted in substantial hotspots in rectal RBE weighted dose. For AO IMPT, it was typically not possible to find a plan that simultaneously met the tumor and rectal constraints for both fixed and variable RBE models. CONCLUSION: If either a fixed RBE of 1.1 or a variable RBE model could be validated in vivo, then it would always be possible to use AO IMPT to dose-boost the prostate and improve normal tissue sparing relative to IMRT. For a cohort without rectum spacer gels, this study (1) underlines the importance of resolving the question of proton RBE within the framework of an IMRT versus proton debate for the prostate and (2) highlights that without further LET/RBE model validation, great care must be taken if AO proton fields are to be considered for prostate treatments.

Randomized Clinical Trial Comparing Proton Beam Radiation Therapy with Transarterial Chemoembolization for Hepatocellular Carcinoma: Results of an Interim Analysis.

PURPOSE: To describe results of a planned interim analysis of a prospective, randomized clinical trial developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Eligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria. Patients were randomly assigned to transarterial chemoembolization (TACE) or to proton beam radiation therapy. Patients randomized to TACE received at least 1 TACE with additional TACE for persistent disease. Proton beam radiation therapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractions over 3 weeks. The primary endpoint was progression-free survival, with secondary endpoints of overall survival, local tumor control, and treatment-related toxicities as represented by posttreatment days of hospitalization. RESULTS: At the time of this analysis 69 subjects were available for analysis. Of these, 36 were randomized to TACE and 33 to proton. Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days, respectively (P<.001). Ten TACE and 12 proton patients underwent liver transplantation after treatment. Viable tumor identified in the explanted livers after TACE/proton averaged 2.4 and 0.9 cm, respectively. Pathologic complete response after TACE/proton was 10%/25% (P=.38). The 2-year overall survival for all patients was 59%, with no difference between treatment groups. Median survival time was 30 months (95% confidence interval 20.7-39.3 months). There was a trend toward improved 2-year local tumor control (88% vs 45%, P=.06) and progression-free survival (48% vs 31%, P=.06) favoring the proton beam treatment group. CONCLUSIONS: This interim analysis indicates similar overall survival rates for proton beam radiation therapy and TACE. There is a trend toward improved local tumor control and progression-free survival with proton beam. There are significantly fewer hospitalization days after proton treatment, which may indicate reduced toxicity with proton beam therapy.

A patient-specific aperture system with an energy absorber for spot scanning proton beams: Verification for clinical application.

PURPOSE: In the authors' proton therapy system, the patient-specific aperture can be attached to the nozzle of spot scanning beams to shape an irradiation field and reduce lateral fall-off. The authors herein verified this system for clinical application. METHODS: The authors prepared four types of patient-specific aperture systems equipped with an energy absorber to irradiate shallow regions less than 4 g/cm(2). The aperture was made of 3-cm-thick brass and the maximum water equivalent penetration to be used with this system was estimated to be 15 g/cm(2). The authors measured in-air lateral profiles at the isocenter plane and integral depth doses with the energy absorber. All input data were obtained by the Monte Carlo calculation, and its parameters were tuned to reproduce measurements. The fluence of single spots in water was modeled as a triple Gaussian function and the dose distribution was calculated using a fluence dose model. The authors compared in-air and in-water lateral profiles and depth doses between calculations and measurements for various apertures of square, half, and U-shaped fields. The absolute doses and dose distributions with the aperture were then validated by patient-specific quality assurance. Measured data were obtained by various chambers and a 2D ion chamber detector array. RESULTS: The patient-specific aperture reduced the penumbra from 30% to 70%, for example, from 34.0 to 23.6 mm and 18.8 to 5.6 mm. The calculated field width for square-shaped apertures agreed with measurements within 1 mm. Regarding patient-specific aperture plans, calculated and measured doses agreed within -0.06% ± 0.63% (mean ± SD) and 97.1% points passed the 2%-dose/2 mm-distance criteria of the γ-index on average. CONCLUSIONS: The patient-specific aperture system improved dose distributions, particularly in shallow-region plans.

Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles.

PURPOSE: The outcome of radiotherapy can be further improved by combining irradiation with dose enhancers such as high-Z nanoparticles. Since 2004, spectacular results have been obtained when low-energy x-ray irradiations have been combined with nanoparticles. Recently, the same combination has been explored in hadron therapy. In vitro studies have shown a significant amplification of the biological damage in tumor cells charged with nanoparticles and irradiated with fast ions. This has been attributed to the increase in the ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement. However, this subject is still a matter of controversy. Within this context, the main goal of the authors' work was to provide new insights into the dose enhancement effects of nanoparticles in proton therapy. METHODS: For this purpose, Monte Carlo calculations (gate/geant4 code) were performed. In particular, the geant4-DNA toolkit, which allows the modeling of early biological damages induced by ionizing radiation at the DNA scale, was used. The nanometric radial energy distributions around the nanoparticle were studied, and the processes (such as Auger deexcitation or dissociative electron attachment) participating in the dose deposition of proton therapy treatments in the presence of nanoparticles were evaluated. It has been reported that the architecture of Monte Carlo calculations plays a crucial role in the assessment of nanoparticle dose enhancement and that it may introduce a bias in the results or amplify the possible final dose enhancement. Thus, a dosimetric study of different cases was performed, considering Au and Gd nanoparticles, several nanoparticle sizes (from 4 to 50 nm), and several beam configurations (source-nanoparticle distances and source sizes). RESULTS: This Monte Carlo study shows the influence of the simulations' parameters on the local dose enhancement and how more realistic configurations lead to a negligible increase of local energy deposition. The obtained dose enhancement factor was up to 1.7 when the source was located at the nanoparticle surface. This dose enhancement was reduced when the source was located at further distances (i.e., in more realistic situations). Additionally, no significant increase in the dissociative electron attachment processes was observed. CONCLUSIONS: The authors' results indicate that physical effects play a minor role in the amplification of damage, as a very low dose enhancement or increase of dissociative electron attachment processes is observed when the authors get closer to more realistic simulations. Thus, other effects, such as biological or chemical processes, may be mainly responsible for the enhanced radiosensibilization observed in biological studies. However, more biological studies are needed to verify this hypothesis.