Andrzej Kacperek

A small-body portable graphite calorimeter for dosimetry in low-energy clinical proton beams

Calorimetry has been recommended and performed in proton beams for some time, but never has graphite calorimetry been used as a reference dosimeter in clinical proton beams. Furthermore, only a few calorimetry measurements have been reported in ocular proton beams. In this paper we describe the construction and performance of a small-body portable graphite calorimeter for clinical low-energy proton beams. Perturbation correction factors for the gap effect, volume averaging effect, heat transfer phenomena and impurity effect are calculated and applied in a comparison with ionization chamber dosimetry following IAEA TRS-398. The ratio of absorbed dose to water obtained from the calorimeter measurements and from the ionization measurements varied between 0.983 and 1.019, depending on the beam type and the ionization chamber calibration modality. Standard uncertainties on these values varied between 1.9% and 2.5% including a substantial contribution from the kQ values in IAEA TRS-398. The (Wair/e)p values inferred from these measurements varied between 33.6 J C(-1) and 34.9 J C(-1) with similar standard uncertainties. A number of improvements for the small-body portable graphite calorimeter and the experimental set-up are suggested for potential reduction of the uncertainties.

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 physics of Cerenkov light production during proton therapy

There is increasing interest in using Cerenkov emissions for quality assurance and in vivo dosimetry in photon and electron therapy. Here, we investigate the production of Cerenkov light during proton therapy and its potential applications in proton therapy. A primary proton beam does not have sufficient energy to generate Cerenkov emissions directly, but we have demonstrated two mechanisms by which such emissions may occur indirectly: (1) a fast component from fast electrons liberated by prompt gamma (99.13%) and neutron (0.87%) emission; and (2) a slow component from the decay of radioactive positron emitters. The fast component is linear with dose and doserate but carries little spatial information; the slow component is non-linear but may be localised. The properties of the two types of emission are explored using Monte Carlo modelling in GEANT4 with some experimental verification. We propose that Cerenkov emissions could contribute to the visual sensation reported by some patients undergoing proton therapy of the eye and we discuss the feasibility of some potential applications of Cerenkov imaging in proton therapy.

Whole anterior segment proton beam radiotherapy for diffuse iris melanoma

Aim To report the results of whole anterior segment proton beam radiotherapy (PBR) for diffuse iris melanoma. Methods Between 2000 and 2011, 12 patients with iris melanoma received PBR to the entire iris and ciliary body. Results Patients had a mean age of 57 years and a median follow-up of 3.5 years (range 1–11.6 years). Tumour iris involvement was 1–4 h in five patients, 5–8 h in four and 9–12 h in three. Angle involvement was 6–8 h in five patients and 9–12 h in seven. The visual acuity (VA) before treatment was 6/5–6/6 in six patients, 6/8–6/9 in three and 6/18–6/38 in three. No tumour recurrence occurred during the follow-up period. Glaucoma treatment was required in 11 of 12 patients. The visual acuity at the last follow-up was 6/5–6/9 in five patients, 6/18–6/24 in three, 6/60–1/60 in two and no light perception in two. Four patients developed varying non-severe degrees of limbal stem cell deficiency, which was treatable with conservative measures. Conclusions Whole anterior segment PBR is a useful alternative to enucleation for diffuse iris melanoma. Most patients will need treatment for glaucoma and some may require treatment for tear-film instability and/or stem cell failure.

Practice Patterns Analysis of Ocular Proton Therapy Centers: The International OPTIC Survey.

PURPOSE To assess the planning, treatment, and follow-up strategies worldwide in dedicated proton therapy ocular programs. METHODS AND MATERIALS Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow. RESULTS Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers (P=.0161). Generally, ophthalmologists followed up the post-radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers. CONCLUSIONS The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients.

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.

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.

Fluence correction factors for graphite calorimetry in a low-energy clinical proton beam: I. Analytical and Monte Carlo simulations

The conversion of absorbed dose-to-graphite in a graphite phantom to absorbed dose-to-water in a water phantom is performed by water to graphite stopping power ratios. If, however, the charged particle fluence is not equal at equivalent depths in graphite and water, a fluence correction factor, kfl, is required as well. This is particularly relevant to the derivation of absorbed dose-to-water, the quantity of interest in radiotherapy, from a measurement of absorbed dose-to-graphite obtained with a graphite calorimeter. In this work, fluence correction factors for the conversion from dose-to-graphite in a graphite phantom to dose-to-water in a water phantom for 60 MeV mono-energetic protons were calculated using an analytical model and five different Monte Carlo codes (Geant4, FLUKA, MCNPX, SHIELD-HIT and McPTRAN.MEDIA). In general the fluence correction factors are found to be close to unity and the analytical and Monte Carlo codes give consistent values when considering the differences in secondary particle transport. When considering only protons the fluence correction factors are unity at the surface and increase with depth by 0.5% to 1.5% depending on the code. When the fluence of all charged particles is considered, the fluence correction factor is about 0.5% lower than unity at shallow depths predominantly due to the contributions from alpha particles and increases to values above unity near the Bragg peak. Fluence correction factors directly derived from the fluence distributions differential in energy at equivalent depths in water and graphite can be described by kfl = 0.9964 + 0.0024·zw-eq with a relative standard uncertainty of 0.2%. Fluence correction factors derived from a ratio of calculated doses at equivalent depths in water and graphite can be described by kfl = 0.9947 + 0.0024·zw-eq with a relative standard uncertainty of 0.3%. These results are of direct relevance to graphite calorimetry in low-energy protons but given that the fluence correction factor is almost solely influenced by non-elastic nuclear interactions the results are also relevant for plastic phantoms that consist of carbon, oxygen and hydrogen atoms as well as for soft tissues.

Prognostic Biopsy of Choroidal Melanoma after Proton Beam Radiation Therapy

Figure 1. Metastatic mortality according to chromosome 3 status. Choroidal melanoma is fatal in almost 50% of patients. A large majority of patients with this cancer want to know their prognosis, even if there is no effective treatment for metastatic disease. Those with a good prognosis are reassured. Special measures, such as more intensive surveillance, can be targeted at high-risk patients, who either may ultimately undergo liver surgery or be given systemic or localized hepatic chemotherapy. Metastatic disease develops almost exclusively in patients whose tumor shows chromosome 3 loss, with or without changes in chromosome 8q, and/or a class 2 gene expression profile. Genetic tumor analysis greatly enhances estimation of survival probability, especially if clinical and histologic predictors are included in the multivariate analysis. Most patients are treated with proton beam radiotherapy (PBR) or plaque brachytherapy, so that biopsy is required for prognostication. Complications, such as vitreous hemorrhage, can complicate the radiotherapy treatment; furthermore, there are concerns that the biopsy might seed the tumor to other parts of the eye and extraocularly. For these reasons, for several years we have offered patients prognostic tumor biopsy after radiotherapy. The aim of this study was to correlate metastatic mortality with multiplex ligationdependent probe amplification (MLPA) or microsatellite analysis (MSA) performed on choroidal melanoma biopsy samples obtained soon after completion of PBR. Patients were included if they resided in the UK and had a successful transretinal biopsy of choroidal melanoma within 1 month of PBR completion. The National Health Service Cancer Registry is populated with every patient with a staged tumor diagnosis; the registry is commissioned to report to the referring oncology unit at the time of death, along with the death certificate issued by local physicians, and it is from this registry that survival data were obtained. Proton beam radiotherapy (56 Gy over 4 consecutive days) was administered at the Clatterbridge Cancer Center, located 14 km from the Liverpool Ocular Oncology Center, where all ophthalmic care was delivered. Biopsy was performed as soon as possible after PBR. Tumor samples were obtained with a 25-gauge vitreous cutter, the cytospin stained with May Grunewald Giemsa, and assessed histologically by an experienced ophthalmic pathologist (S.E.C.) for cell content and type. DNA extraction, DNA quality assessment and quantification and identification of chromosome aberrations by MLPA or MSA were performed as described previously. This study was conducted in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice Guidelines. The service evaluation was approved by the Royal Liverpool and Broadgreen University Hospital Trust (Reference number: TA0517). The study cohort included 102 patients, who comprised 47 females and 55 males with a mean age of 57.3 years (range, 25e82; Table 1, available at www.aaojournal.org). The tumors had a mean largest basal diameter 12.0 mm (range, 5.4e19.3) and a median tumor thickness of 3.5 mm (range, 0.9e10.3). Twentyfour tumors involved the ciliary body and 8 extended to anterior chamber and angle. Tumor biopsy was performed on the last day of PBR treatment in 70 patients (69%), after 1 through 7 days in 28 patients, and 8 through 20 days in 4 patients. Diagnosis of melanoma was confirmed cytologically in all cases (Fig 2, available at www.aaojournal.org). Genetic analysis was performed by MLPA in 74 patients and MSA in 28 cases. Chromosomal analysis demonstrated monosomy 3 in 39 (38%) and disomy 3 in 63 (62%). Other chromosomal alterations included chr.6p gain in 49%, chr.8q gain in 40%, and chr.1p loss in 16%. The median follow-up was 3.6 years (range, 0.3e8.6). By study close, 12 patients died (11.8%), 9 from metastatic disease. Actuarial rates of metastatic death at 7 years were 0% in disomy 3 patients and 35% in monosomy 3 patients (Fig 1). To our knowledge, this is the largest study yet performed on genetic typing of choroidal melanoma samples obtained after radiotherapy. We previously compared preradiotherapy and postradiotherapy MLPA/MSA data from the same tumors in 4 patients, showing concordance in all tumors. Similarly, array CGH of 5 tumors preradiotherapy and postradiotherapy showed no change in chromosome 3 status because of treatment. Dogrusöz et al performed karyotyping and/or fluorescence in-situ hybridization in 36 enucleated eyes with previously irradiated choroidal melanoma and found frequent, complex and extensive chromosomal abnormalities in irradiated tumors. Their genetic studies were performed many months after radiotherapy, when tumors had developed necrosis and inflammation and when clonal expansion of any surviving melanoma cells may have occurred; therefore, their results cannot be extrapolated to our tumors, which were biopsied within a month of PBR.

Issues involved in the quantitative 3D imaging of proton doses using optical CT and chemical dosimeters

Abstract Dosimetry of proton beams using 3D imaging of chemical dosimeters is complicated by a variation with proton linear energy transfer (LET) of the dose–response (the so-called ‘quenching effect’). Simple theoretical arguments lead to the conclusion that the total absorbed dose from multiple irradiations with different LETs cannot be uniquely determined from post-irradiation imaging measurements on the dosimeter. Thus, a direct inversion of the imaging data is not possible and the proposition is made to use a forward model based on appropriate output from a planning system to predict the 3D response of the dosimeter. In addition to the quenching effect, it is well known that chemical dosimeters have a non-linear response at high doses. To the best of our knowledge it has not yet been determined how this phenomenon is affected by LET. The implications for dosimetry of a number of potential scenarios are examined. Dosimeter response as a function of depth (and hence LET) was measured for four samples of the radiochromic plastic PRESAGE®, using an optical computed tomography readout and entrance doses of 2.0 Gy, 4.0 Gy, 7.8 Gy and 14.7 Gy, respectively. The dosimeter response was separated into two components, a single-exponential low-LET response and a LET-dependent quenching. For the particular formulation of PRESAGE® used, deviations from linearity of the dosimeter response became significant for doses above approximately 16 Gy. In a second experiment, three samples were each irradiated with two separate beams of 4 Gy in various different configurations. On the basis of the previous characterizations, two different models were tested for the calculation of the combined quenching effect from two contributions with different LETs. It was concluded that a linear superposition model with separate calculation of the quenching for each irradiation did not match the measured result where two beams overlapped. A second model, which used the concept of an ‘effective dose’ matched the experimental results more closely. An attempt was made to measure directly the quench function for two proton beams as a function of all four variables of interest (two physical doses and two LET values). However, this approach was not successful because of limitations in the response of the scanner.