Side Effects of Proton Beam Radiotherapy Treatment on Iris Melanoma.

PURPOSE: This study evaluated the functional outcome and ocular side effects of patients receiving proton beam radiotherapy (PBR) for the treatment of iris melanoma (IM). DESIGN: This retrospective study analyzed prospectively collected data. PARTICIPANTS: Patients with IM who underwent PBR as a primary treatment. METHODS: Treatment was given in the form of whole PBR (wPBR: n = 51) or segmental PBR (sPBR: n = 98). MAIN OUTCOME MEASURES: Visual acuity (VA) and side effects were divided into ocular surface disease (OSD), secondary glaucoma, or cataract development. RESULTS: A total of 149 eyes of 149 patients with a mean age of 53.9 ± 16.0 years were included. Tumor recurrence developed in 3 patients (wPBR: 1/51; sPBR: 2/98). Ocular surface disease was observed in 78.4% of the wPBR group (40/51) and 25.5% of the sPBR group (25/98) (P < 0.001) after 0.7 ± 1.2 years and 1.1 ± 0.9 years, respectively. The main side effect was dry eye syndrome in both groups, but severe side effects such as limbal stem cell failure were found only in the wPBR group (4/51; 7.8%). Secondary glaucoma developed in 31.4% of the wPBR group (16/51) compared with 1.0% in the sPBR group (1/98; P < 0.001). Glaucoma control was generally achieved with eye drops, whereas surgery was necessary in 5 patients (wPBR: 4/51, 7.8%; sPBR: 1/98, 1%). Cataract surgery was performed in 47.9% of the wPBR group (23/48) and 19.8% of the sPBR group (19/96) (P < 0.001). Before treatment, VA was 0.14 ± 0.27 logarithm of the minimum angle of resolution (logMAR) in the wPBR group and 0.04 ± 0.19 logMAR in the sPBR group. A worsening was seen in the wPBR group (0.55 ± 0.16 logMAR; P < 0.001) 6 months after radiotherapy, which normalized after 12 months (0.15 ± 0.30 logMAR; P = 0.17). In the sPBR group, no such decrease in VA was observed (6 months: 0.03 ± 0.22 logMAR, P = 0.54; 12 months: 0.04 ± 0.21 logMAR, P = 0.98). CONCLUSIONS: Our results demonstrate that PBR is a very successful treatment option for patients with IM, showing a high tumor control rate and relatively low complication profile. Tumor recurrence was a rare event, and secondary enucleation was not necessary in any patient. Side effects are commonly seen, but severe side effects such as limbal stem cell failure or secondary glaucoma mainly developed after wPBR. These results are important for clinical decision making and discussion with the patient regarding this form of radiotherapy. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Quality assurance in proton beam therapy using a plastic scintillator and a commercially available digital camera.

PURPOSE: In this article, we evaluate a plastic scintillation detector system for quality assurance in proton therapy using a BC-408 plastic scintillator, a commercial camera, and a computer. METHODS: The basic characteristics of the system were assessed in a series of proton irradiations. The reproducibility and response to changes of dose, dose-rate, and proton energy were determined. Photographs of the scintillation light distributions were acquired, and compared with Geant4 Monte Carlo simulations and with depth-dose curves measured with an ionization chamber. A quenching effect was observed at the Bragg peak of the 60 MeV proton beam where less light was produced than expected. We developed an approach using Birks equation to correct for this quenching. We simulated the linear energy transfer (LET) as a function of depth in Geant4 and found Birks constant by comparing the calculated LET and measured scintillation light distribution. We then used the derived value of Birks constant to correct the measured scintillation light distribution for quenching using Geant4. RESULTS: The corrected light output from the scintillator increased linearly with dose. The system is stable and offers short-term reproducibility to within 0.80%. No dose rate dependency was observed in this work. CONCLUSIONS: This approach offers an effective way to correct for quenching, and could provide a method for rapid, convenient, routine quality assurance for clinical proton beams. Furthermore, the system has the advantage of providing 2D visualization of individual radiation fields, with potential application for quality assurance of complex, time-varying fields.

PTCOG Ocular Statement: Expert Summary of Current Practices and Future Developments in Ocular Proton Therapy.

Although rare cancers, ocular tumors are a threat to vision, quality of life, and potentially life expectancy of a patient. Ocular proton therapy (OPT) is a powerful tool for successfully treating this disease. The Particle Therapy Co-Operative Ocular Group (PTCOG Ocular) formulated an Evidence and Expert-Based Executive Summary of Current Practices and Future Developments in OPT: Comparative dosimetric and clinical analysis with the different OPT systems is essential to set up planning guidelines, implement best practices, and establish benchmarks for eye preservation, vision, and quality of life measures. Contemporary prospective trials in select subsets of patients (e.g., tumors near the optic disc and/or macula) may allow for dosimetric and clinical analysis between different radiation modalities and beamline systems to evaluate differences in radiation delivery and penumbra, and resultant tumor control, normal tissue complication rates, and overall clinical cost-effectiveness. To date, the combination of multimodal imaging (fundus photography, ultrasound, etc.), ophthalmologist assessment, and clip surgery with radiation planning have been keys to successful treatment. Increased use of 3D imaging (CT/MRI) is anticipated although its spatial resolution might be a limiting factor (e.g., detection of flat diffuse tumor parts). Commercially produced ocular treatment planning systems are under development and their future use is expected to expand across OPT centers. Future continuity of OPT will depend on (i) maintaining and upgrading existing older dedicated low-energy facilities, (ii) maintaining shared, degraded beamlines at large proton therapy centers, and (iii) developing adapted gantry beams of sufficient quality to maintain the clinical benefits of sharp beam conformity. Option (i) potentially offers the sharpest beams, minimizing impact on healthy tissues, whilst (ii) and (iii) potentially offer the advantage of substantial long-term technical support and development as well as the introduction of new approaches. Significant patient throughputs and close cooperation between medical physics, ophthalmology, and radiotherapy, underpinned by mutual understanding, is crucial for a successful OPT service.

Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence.

Complex DNA damage (CDD), containing two or more DNA lesions within one or two DNA helical turns, is a signature of ionising radiation (IR) and contributes significantly to the therapeutic effect through cell killing. The levels and complexity of CDD increases with linear energy transfer (LET), however, the specific cellular response to this type of DNA damage and the critical proteins essential for repair of CDD is currently unclear. We performed an siRNA screen of ~240 DNA damage response proteins to identify those specifically involved in controlling cell survival in response to high-LET protons at the Bragg peak, compared to low-LET entrance dose protons which differ in the amount of CDD produced. From this, we subsequently validated that depletion of 8-oxoguanine DNA glycosylase (OGG1) and poly(ADP-ribose) glycohydrolase (PARG) in HeLa and head and neck cancer cells leads to significantly increased cellular radiosensitivity specifically following high-LET protons, whilst no effect was observed after low-LET protons and X-rays. We subsequently confirmed that OGG1 and PARG are both required for efficient CDD repair post-irradiation with high-LET protons. Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation.

Spread-out Bragg peak measurements using a compact quality assurance range calorimeter at the Clatterbridge cancer centre.

Objective.The superior dose conformity provided by proton therapy relative to conventional x-ray radiotherapy necessitates more rigorous quality assurance (QA) procedures to ensure optimal patient safety. Practically however, time-constraints prevent comprehensive measurements to be made of the proton range in water: a key parameter in ensuring accurate treatment delivery.Approach.A novel scintillator-based device for fast, accurate water-equivalent proton range QA measurements for ocular proton therapy is presented. Experiments were conducted using a compact detector prototype, the quality assurance range calorimeter (QuARC), at the Clatterbridge cancer centre (CCC) in Wirral, UK for the measurement of pristine and spread-out Bragg peaks (SOBPs). The QuARC uses a series of 14 optically-isolated 100 × 100 × 2.85 mm polystyrene scintillator sheets, read out by a series of photodiodes. The detector system is housed in a custom 3D-printed enclosure mounted directly to the nozzle and a numerical model was used to fit measured depth-light curves and correct for scintillator light quenching.Main results.Measurements of the pristine 60 MeV proton Bragg curve found the QuARC able to measure proton ranges accurate to 0.2 mm and reduced QA measurement times from several minutes down to a few seconds. A new framework of the quenching model was deployed to successfully fit depth-light curves of SOBPs with similar range accuracy.Significance.The speed, range accuracy and simplicity of the QuARC make the device a promising candidate for ocular proton range QA. Further work to investigate the performance of SOBP fitting at higher energies/greater depths is warranted.

USP9X Is Required to Maintain Cell Survival in Response to High-LET Radiation.

Ionizing radiation (IR) principally acts through induction of DNA damage that promotes cell death, although the biological effects of IR are more broad ranging. In fact, the impact of IR of higher-linear energy transfer (LET) on cell biology is generally not well understood. Critically, therefore, the cellular enzymes and mechanisms responsible for enhancing cell survival following high-LET IR are unclear. To this effect, we have recently performed siRNA screening to identify deubiquitylating enzymes that control cell survival specifically in response to high-LET α-particles and protons, in comparison to low-LET X-rays and protons. From this screening, we have now thoroughly validated that depletion of the ubiquitin-specific protease 9X (USP9X) in HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells using small interfering RNA (siRNA), leads to significantly decreased survival of cells after high-LET radiation. We consequently investigated the mechanism through which this occurs, and demonstrate that an absence of USP9X has no impact on DNA damage repair post-irradiation nor on apoptosis, autophagy, or senescence. We discovered that USP9X is required to stabilize key proteins (CEP55 and CEP131) involved in centrosome and cilia formation and plays an important role in controlling pericentrin-rich foci, particularly in response to high-LET protons. This was also confirmed directly by demonstrating that depletion of CEP55/CEP131 led to both enhanced radiosensitivity of cells to high-LET protons and amplification of pericentrin-rich foci. Our evidence supports the importance of USP9X in maintaining centrosome function and biogenesis and which is crucial particularly in the cellular response to high-LET radiation.

Local tumour control and radiation side effects for fractionated stereotactic photon beam radiotherapy compared to proton beam radiotherapy in uveal melanoma.

PURPOSE: To compare the adverse side effects of fractionated stereotactic photon beam radiotherapy (fSRT) with proton beam radiotherapy (PBR) in patients with uveal melanoma (UM). METHODS: A retrospective study investigating 306 UM patients treated with fSRT (N=153) by the Rotterdam Ocular Melanoma Study group (ROMS), The Netherlands, between 1999-2014 or with PBR (N=153) at the Royal Liverpool University Hospital and the Clatterbridge Cancer Centre, Bebington, United Kingdom, between 1993-2014. The tumours treated with fSRT were matched with tumours treated with PBR based on sex, left or right eye, TNM classification, posterior margin ≤ or > 3mm of the fovea and of the optic disc. RESULTS: The five-year actuarial rates of tumour recurrence were 4.5% for fSRT and 6.1% for PBR. For fSRT and PBR, the five-year actuarial rates of maculopathy were 14.9% and 12.4%, and for vitreous haemorrhage were 29.4% and 4.7%, respectively. Only vitreous haemorrhage (HR: 0.19, 95% CI: 0.07-0.56) was more common after fSRT compared to PBR. Overall, larger tumours were risk factors for maculopathy and secondary enucleation. CONCLUSIONS: Both treatments have excellent local tumour control. In matched groups, vitreous haemorrhage was the only adverse side effect showing a significant difference between groups.

Targeting DNA Double-Strand Break Repair Enhances Radiosensitivity of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma to Photons and Protons.

The response of head and neck squamous cell carcinoma (HNSCC) to radiotherapy depends on human papillomavirus type 16 (HPV) status, and where improved outcome and survival is observed in HPV-positive disease. However, strategies to further radiosensitise the tumours, particularly relatively radioresistant HPV-negative HNSCC, are actively being sought. The impact of targeting the major protein kinases involved in the signaling of DNA double-strand break (DSB) repair, namely ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), and the catalytic subunit of DNA-dependent protein kinase (DNA-Pkcs), on the radiosensitisation of HNSCC cells was examined. The response to both conventional photon radiotherapy, but also proton beam therapy, was analysed by clonogenic assays and 3D spheroid growth. We observed that inhibition of ATM, ATR, and particularly DNA-Pkcs, caused a significant reduction in HNSCC cell survival post-irradiation with both photons and protons, with less of an impact on the most radiosensitive HPV-positive cell line. The inhibition of DNA-Pkcs and, to a lesser extent ATM, in combination with radiation was also more effective at inhibiting the growth of 3D spheroids derived from relatively radioresistant HPV-negative HNSCC. Similar effects of the inhibitors were observed comparing photon and proton irradiation, demonstrating the potential for targeting DSB repair as an effective combination treatment for HNSCC.

Beam characterisation studies of the 62 MeV proton therapy beamline at the Clatterbridge Cancer Centre.

The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world's first hospital proton beam therapy facility, providing treatment for ocular cancers since 1989. A 62 MeV beam of protons is produced by a Scanditronix cyclotron and transported through a passive delivery system. In addition to the long history of clinical use, the facility supports a wide programme of experimental work and as such, an accurate and reliable simulation model of the treatment beamline is highly valuable. However, as the facility has seen several changes to the accelerator and beamline over the years, a comprehensive study of the CCC beam dynamics is needed to firstly examine the beam optics. An extensive analysis was required to overcome facility related constraints to determine fundamental beamline parameters and define an optical lattice written with the Methodical Accelerator Design (MAD-X) and the particle tracking Beam Delivery Simulation (BDSIM) code. An optimised case is presented and simulated results of the optical functions, beam distribution, losses and the transverse rms beam sizes along the beamline are discussed. Corresponding optical and beam information was used in TOPAS to simulate transverse beam profiles and compared to EBT3 film measurements. We provide an overview of the magnetic components, beam transport, cyclotron, beam and treatment related parameters necessary for the development of a present day optical model of the facility. This work represents the first comprehensive study of the CCC facility to date, as a basis to determine input beam parameters to accurately simulate and completely characterise the beamline.

Effects of plaque brachytherapy and proton beam radiotherapy on prognostic testing: a comparison of uveal melanoma genotyped by microsatellite analysis.

BACKGROUND/AIMS: Proton beam radiotherapy and plaque brachytherapy are commonly applied in primary uveal melanoma (UM); however, their effect on chromosome 3 classification of UM by microsatellite analysis (MSA) for prognostication purposes is unknown, where the tumour is sampled post-irradiation. This study examined the prognostic accuracy of genotyping UM biopsied before or after administration of radiotherapy, by MSA. METHODS: 407 UM patients treated at the Liverpool Ocular Oncology Centre between January 2011 to December 2017, were genotyped for chromosome 3 by MSA; 172 and 176 primary UM were sampled prior to and post irradiation, respectively. RESULTS: Genotyping by MSA was successful in 396/407 (97%) of UM samples (196 males, 211 females; median age of 61 years (range 12 to 93) at primary treatment). There was no demonstrable association between a failure of MSA to produce a chromosome 3 classification and whether radiation was performed pre-biopsy or post-biopsy with an OR of 0.96 (95% CI 0.30 to 3.00, p=0.94). There was no evidence of association (measured as HRs) between risk of metastatic death and sampling of a primary UM before administration of radiotherapy (HR 1.1 (0.49 to 2.50), p=0.81). Monosomy 3 (HR 12.0 (4.1 to 35.0), p<0.001) was significantly associated with increased risk of metastatic death. CONCLUSIONS AND RELEVANCE: This study revealed that successful genotyping of UM using MSA is possible, irrespective of irradiation status. Moreover, we found no evidence that biopsy prior to radiotherapy increases metastatic mortality.

Practice Considerations for Proton Beam Radiation Therapy of Uveal Melanoma During the Coronavirus Disease Pandemic: Particle Therapy Co-Operative Group Ocular Experience.

Uveal melanoma (UM) is a rare but life-threatening cancer of the eye. In light of the coronavirus disease (COVID-19) pandemic, hospitals and proton eye therapy facilities must analyze several factors to ensure appropriate treatment protocols for patients and provider teams. Practice considerations to limit COVID-19 transmission in the proton ocular treatment setting for UM are necessary. The Particle Therapy Co-Operative Group is the largest international community of particle/proton therapy providers. Participating experts have current or former affiliation with the member institutions of the Particle Therapy Co-Operative Group Ocular subcommittee with long-standing high-volume proton ocular programs. The practices reviewed in this document must be taken in conjunction with local hospital procedures, multidisciplinary recommendations, and regional/national guidelines, as each community may have its unique needs, supplies, and protocols. Importantly, as the pandemic evolves, so will the strategies and recommendations. Given the unique circumstances for UM patients, along with indications of potential ophthalmologic transmission as a result of health care providers working in close proximity to patients and intrinsic infectious risk from eyelashes, tears, and hair, practice strategies may be adapted to reduce the risk of viral transmission. Certainly, providers and health care systems will continue to examine and provide as safe and effective care as possible for patients in the current environment.

Characterisation of Deubiquitylating Enzymes in the Cellular Response to High-LET Ionizing Radiation and Complex DNA Damage.

PURPOSE: Ionizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking. METHODS AND MATERIALS: A small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay. RESULTS: Depletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA. CONCLUSIONS: USP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.

Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response.

PURPOSE: To investigate the precise mechanism of recognition and processing of ionizing radiation (IR)-induced complex DNA damage (CDD), where two or more DNA lesions are in close proximity, in cellular DNA which is packaged with histones to form chromatin. METHODS AND MATERIALS: HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A and UMSCC6) cells were irradiated with high linear energy transfer (LET) α-particles or protons, versus low-LET protons and X rays. At various time points after irradiation, site-specific histone post-translational modifications were analyzed by quantitative Western blotting; DNA damage and repair were measured by different versions of the comet assay; and cell survival was determined using clonogenic assays. RESULTS: Site-specific histone post-translational modifications after low- and high-LET radiation, particularly proton irradiation, were screened, aiming to identify those responsive to CDD. We demonstrate that histone H2B ubiquitylated on lysine 120 (H2Bub) is specifically induced several hours after irradiation in response to high-LET α-particles and protons but not by low-LET protons or X rays/γ-radiation. This is associated with increased levels of CDD, which contributes to decreased cell survival. We further discovered that modulation of H2Bub is under the control of two E3 ubiquitin ligases, MSL2 and RNF20/RNF40 complex, whose depletion leads to defective processing and further persistence of CDD, and to additional decreased cell survival after irradiation. CONCLUSION: This study demonstrates that the signaling and repair of CDD, particularly induced by high-LET IR is co-ordinated through the specific induction of H2Bub catalyzed by MSL2 and RNF20/40, a mechanism that contributes significantly to cell survival after irradiation.

Response of synthetic diamond detectors in proton, carbon, and oxygen ion beams.

PURPOSE: In this work, the LET-dependence of the response of synthetic diamond detectors is investigated in different particle beams. METHOD: Measurements were performed in three nonmodulated particle beams (proton, carbon, and oxygen). The response of five synthetic diamond detectors was compared to the response of a Markus or an Advanced Markus ionization chamber. The synthetic diamond detectors were used with their axis parallel to the beam axis and without any bias voltage. A high bias voltage was applied to the ionization chambers, to minimize ion recombination, for which no correction is applied (+300 V and +400 V were applied to the Markus and Advanced Markus ionization chambers respectively). RESULTS: The ratio between the normalized response of the synthetic diamond detectors and the normalized response of the ionization chamber shows an under-response of the synthetic diamond detectors in carbon and oxygen ion beams. No under-response of the synthetic diamond detectors is observed in protons. For each beam, combining results obtained for the five synthetic diamond detectors and considering the uncertainties, a linear fit of the ratio between the normalized response of the synthetic diamond detectors and the normalized response of the ionization chamber is determined. The response of the synthetic diamond detectors can be described as a function of LET as (-6.22E-4 ± 3.17E-3) • LET + (0.99 ± 0.01) in proton beam, (-2.51E-4 ± 1.18E-4) • LET + (1.01 ± 0.01) in carbon ion beam and (-2.77E-4 ± 0.56E-4) • LET + (1.03 ± 0.01) in oxygen ion beam. Combining results obtained in carbon and oxygen ion beams, a LET dependence of about 0.026% (±0.013%) per keV/µm is estimated. CONCLUSIONS: Due to the high LET value, a LET dependence of the response of the synthetic diamond detector was observed in the case of carbon and oxygen beams. The effect was found to be negligible in proton beams, due to the low LET value. The under-response of the synthetic diamond detector may result from the recombination of electron/hole in the thin synthetic diamond layer, due to the high LET-values. More investigations are required to confirm this assumption.

Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire.

BACKGROUND: We performed a survey using the modified EORTC Facility questionnaire (pFQ) to evaluate the human, technical and organizational resources of particle centers in Europe. MATERIAL AND METHODS: The modified pFQ consisted of 235 questions distributed in 11 sections accessible on line on an EORTC server. Fifteen centers from 8 countries completed the pFQ between May 2015 and December 2015. RESULTS: The average number of patients treated per year and per particle center was 221 (range, 40-557). The majority (66.7%) of centers had pencil beam or raster scanning capability. Four (27%) centers were dedicated to eye treatment only. An increase in the patients-health professional FTE ratio was observed for eye tumor only centers when compared to other centers. All centers treated routinely chordomas/chondrosarcomas, brain tumors and sarcomas but rarely breast cancer. The majority of centers treated pediatric cases with particles. Only a minority of the queried institutions treated non-static targets. CONCLUSIONS: As the number of particle centers coming online will increase, the experience with this treatment modality will rise in Europe. Children can currently be treated in these facilities in a majority of cases. The majority of these centers provide state of the art particle beam therapy.

Ion recombination correction in the Clatterbridge Centre of Oncology clinical proton beam.

Most codes of practice for dosimetry of proton beams do not give a clear recommendation on the determination of recombination correction factors for ionization chambers. In this work, recombination corrections were measured in the low-energy clinical proton beam of the Clatterbridge Centre of Oncology (CCO) using data collected at different dose rates and different polarizing voltages. This approach allows the separation of contributions from initial and volume recombination and was compared with results from extrapolation and two-voltage methods. A modified formulation of the method is presented for a modulated beam in which the ionization current is time dependent. Using a set-up with two identical chambers placed face-to-face yielded highly accurate data for plane-parallel ionization chambers. This method may also be used for high-energy photon and electron beam dosimetry. At typical dose rates of 26 Gy min(-1) used clinically at the CCO, the recombination correction is 0.8% and thus is of importance for reference dosimetry. The proton beam should be treated as purely continuous given the high pulse repetition frequency of the cyclotron beam. The results show that the volume recombination parameter for protons is consistent with values measured for photon beams. Initial recombination was found to be independent of beam quality, except for a tendency to increase at the distal edge of the Bragg peak; this is only relevant for depth dose measurements. Using a general equation for recombination and generic values for the initial and volume recombination parameters (A = 0.25 V and m2 = 3.97 x 10(3) s cm(-1) nC(-1) V2), the experimental results are reproduced within 0.1% for all conditions met in this work. For the CCO beam and similar proton beams used for treating optical targets operating at high dose rates, the recombination correction factor can be overestimated by up to 2%, resulting in an overestimation of dose to water by the same amount, if the recommendation from IAEA TRS-398, which is only valid for pulsed beams, is followed without consideration.

The influence of physical wedges on penumbra and in-field dose uniformity in ocular proton beams.

A physical wedge may be partially introduced into a proton beam when treating ocular tumours in order to improve dose conformity to the distal border of the tumour and spare the optic nerve. Two unwanted effects of this are observed: a predictable broadening of the beam penumbra on the wedged side of the field and, less predictably, an increase in dose within the field along a relatively narrow volume beneath the edge (toe) of the wedge, as a result of small-angle proton scatter. Monte Carlo simulations using MCNPX and direct measurements with radiochromic (GAFCHROMIC(®) EBT2) film were performed to quantify these effects for aluminium wedges in a 60 MeV proton beam as a function of wedge angle and position of the wedge relative to the patient. For extreme wedge angles (60° in eye tissue) and large wedge-to-patient distances (70 mm in this context), the 90-10% beam penumbra increased from 1.9 mm to 9.1 mm. In-field dose increases from small-angle proton scatter were found to contribute up to 21% additional dose, persisting along almost the full depth of the spread-out-Bragg peak. Profile broadening and in-field dose enhancement are both minimised by placing the wedge as close as possible to the patient. Use of lower atomic number wedge materials such as PMMA reduce the magnitude of both effects as a result of a reduced mean scattering angle per unit energy loss; however, their larger physical size and greater variation in density are undesirable.

Experimental and Monte Carlo studies of fluence corrections for graphite calorimetry in low- and high-energy clinical proton beams.

PURPOSE: The aim of this study was to determine fluence corrections necessary to convert absorbed dose to graphite, measured by graphite calorimetry, to absorbed dose to water. Fluence corrections were obtained from experiments and Monte Carlo simulations in low- and high-energy proton beams. METHODS: Fluence corrections were calculated to account for the difference in fluence between water and graphite at equivalent depths. Measurements were performed with narrow proton beams. Plane-parallel-plate ionization chambers with a large collecting area compared to the beam diameter were used to intercept the whole beam. High- and low-energy proton beams were provided by a scanning and double scattering delivery system, respectively. A mathematical formalism was established to relate fluence corrections derived from Monte Carlo simulations, using the fluka code [A. Ferrari et al., "fluka: A multi-particle transport code," in CERN 2005-10, INFN/TC 05/11, SLAC-R-773 (2005) and T. T. Böhlen et al., "The fluka Code: Developments and challenges for high energy and medical applications," Nucl. Data Sheets 120, 211-214 (2014)], to partial fluence corrections measured experimentally. RESULTS: A good agreement was found between the partial fluence corrections derived by Monte Carlo simulations and those determined experimentally. For a high-energy beam of 180 MeV, the fluence corrections from Monte Carlo simulations were found to increase from 0.99 to 1.04 with depth. In the case of a low-energy beam of 60 MeV, the magnitude of fluence corrections was approximately 0.99 at all depths when calculated in the sensitive area of the chamber used in the experiments. Fluence correction calculations were also performed for a larger area and found to increase from 0.99 at the surface to 1.01 at greater depths. CONCLUSIONS: Fluence corrections obtained experimentally are partial fluence corrections because they account for differences in the primary and part of the secondary particle fluence. A correction factor, F(d), has been established to relate fluence corrections defined theoretically to partial fluence corrections derived experimentally. The findings presented here are also relevant to water and tissue-equivalent-plastic materials given their carbon content.

Variations in the Processing of DNA Double-Strand Breaks Along 60-MeV Therapeutic Proton Beams.

PURPOSE: To investigate the variations in induction and repair of DNA damage along the proton path, after a previous report on the increasing biological effectiveness along clinically modulated 60-MeV proton beams. METHODS AND MATERIALS: Human skin fibroblast (AG01522) cells were irradiated along a monoenergetic and a modulated spread-out Bragg peak (SOBP) proton beam used for treating ocular melanoma at the Douglas Cyclotron, Clatterbridge Centre for Oncology, Wirral, Liverpool, United Kingdom. The DNA damage response was studied using the 53BP1 foci formation assay. The linear energy transfer (LET) dependence was studied by irradiating the cells at depths corresponding to entrance, proximal, middle, and distal positions of SOBP and the entrance and peak position for the pristine beam. RESULTS: A significant amount of persistent foci was observed at the distal end of the SOBP, suggesting complex residual DNA double-strand break damage induction corresponding to the highest LET values achievable by modulated proton beams. Unlike the directly irradiated, medium-sharing bystander cells did not show any significant increase in residual foci. CONCLUSIONS: The DNA damage response along the proton beam path was similar to the response of X rays, confirming the low-LET quality of the proton exposure. However, at the distal end of SOBP our data indicate an increased complexity of DNA lesions and slower repair kinetics. A lack of significant induction of 53BP1 foci in the bystander cells suggests a minor role of cell signaling for DNA damage under these conditions.