An international film dosimetry intercomparison to establish a multi-center audit framework.

BACKGROUND: In 2021, a Technical Meeting was hosted by the International Atomic Energy Agency (IAEA) where it was recommended that a standardized method for assessing the accuracy of film dose calculations should be established. PURPOSE: To design an audit that evaluates the accuracy of film dosimetry processes. To propose a framework for identifying out-of-tolerance results and to perform an international pilot study to test the audit design. METHODS: Six members of an international Dosimetry Audit Network (DAN) developed an audit for radiochromic film dosimetry. A single host center provided the materials to each participating DAN member to conduct the audits. Materials included: (1) a set of two irradiated audit films (10 Sq: 10 cm × 10 cm, 15 Sq: 15 cm × 15 cm), (2) a reference calibration film set, and (3) a blank sheet of film. The participants were blinded to the dose and tasked with producing dose maps using their standard film dosimetry process. Average Region-Of-Interest (ROI: 2 cm × 2 cm) dose was measured from the dose maps and compared to the known dose. In the audit, all participants used their local scanning and software protocols. Film calibration was performed in two distinct ways: (1) using a calibration film set which was provided by the host center and (2) using a calibration film set which was locally irradiated. Several variations of the audit were also performed to examine how scanning and software processing can affect film dosimetry results. In the first variation of the audit (VariantA), a set of film scans was processed using five different software solutions. In the second variation of the audit (VariantB), all films were scanned on the same scanner and processed using two in-house software solutions. RESULTS: Taking one film scan from each participant, the standard deviations (1σ) (SD) in the dose returned from the host calibration and returned from the local calibration were ±7.2% and ±6.5% respectively, with variations from -12.4% to 12.9% of the known dose. The larger dose variations in the data set were attributed to the corrections applied for variations in scanner brightness during processing and incorrectly assigned calibration doses. When the raw image data set was processed by an expert user of each software solution (VariantA) the SDs were ±2.7% and ±3.7% for in-house and vendor-based software, respectively. When the films were scanned on a single scanner and processed with the two in-house software solutions (VariantB) the results had a SD of ±2.3%. CONCLUSIONS: An audit has been designed and tested for radiotherapy film dosimetry at an international level. A framework for diagnosing issues within a film dosimetry process has been proposed that could be used to audit centers that use film as a dosimeter. Incorporating quality assurance throughout the film process is important in obtaining accurate and consistent film dosimetry. A better understanding of vendor-based software systems is necessary for users to process accurate and consistent film dosimetry.

On dosimetric characteristics of detectors for relative dosimetry in small fields: a multicenter experimental study.

Objective. In this multicentric collaborative study, we aimed to verify whether the selected radiation detectors satisfy the requirements of TRS-483 Code of Practice for relative small field dosimetry in megavoltage photon beams used in radiotherapy, by investigating four dosimetric characteristics. Furthermore, we intended to analyze and complement the recommendations given in TRS-483.Approach. Short-term stability, dose linearity, dose-rate dependence, and leakage were determined for 17 models of detectors considered suitable for small field dosimetry. Altogether, 47 detectors were used in this study across ten institutions. Photon beams with 6 and 10 MV, with and without flattening filters, generated by Elekta Versa HDTMor Varian TrueBeamTMlinear accelerators, were used.Main results. The tolerance level of 0.1% for stability was fulfilled by 70% of the data points. For the determination of dose linearity, two methods were considered. Results from the use of a stricter method show that the guideline of 0.1% for dose linearity is not attainable for most of the detectors used in the study. Following the second approach (squared Pearson's correlation coefficientr2), it was found that 100% of the data fulfill the criteriar2> 0.999 (0.1% guideline for tolerance). Less than 50% of all data points satisfied the published tolerance of 0.1% for dose-rate dependence. Almost all data points (98.2%) satisfied the 0.1% criterion for leakage.Significance. For short-term stability (repeatability), it was found that the 0.1% guideline could not be met. Therefore, a less rigorous criterion of 0.25% is proposed. For dose linearity, our recommendation is to adopt a simple and clear methodology and to define an achievable tolerance based on the experimental data. For dose-rate dependence, a realistic criterion of 1% is proposed instead of the present 0.1%. Agreement was found with published guidelines for background signal (leakage).

Enhancement of Radiation Sensitivity by Cathepsin L Suppression in Colon Carcinoma Cells.

Cancer is one of the main causes of death globally. Radiotherapy/Radiation therapy (RT) is one of the most common and effective cancer treatments. RT utilizes high-energy radiation to damage the DNA of cancer cells, leading to their death or impairing their proliferation. However, radiation resistance remains a significant challenge in cancer treatment, limiting its efficacy. Emerging evidence suggests that cathepsin L (cath L) contributes to radiation resistance through multiple mechanisms. In this study, we investigated the role of cath L, a member of the cysteine cathepsins (caths) in radiation sensitivity, and the potential reduction in radiation resistance by using the specific cath L inhibitor (Z-FY(tBu)DMK) or by knocking out cath L with CRISPR/Cas9 in colon carcinoma cells (caco-2). Cells were treated with different doses of radiation (2, 4, 6, 8, and 10), dose rate 3 Gy/min. In addition, the study conducted protein expression analysis by western blot and immunofluorescence assay, cytotoxicity MTT, and apoptosis assays. The results demonstrated that cath L was upregulated in response to radiation treatment, compared to non-irradiated cells. In addition, inhibiting or knocking out cath L led to increased radiosensitivity in contrast to the negative control group. This may indicate a reduced ability of cancer cells to recover from radiation-induced DNA damage, resulting in enhanced cell death. These findings highlight the possibility of targeting cath L as a therapeutic strategy to enhance the effectiveness of RT. Further studies are needed to elucidate the underlying molecular mechanisms and to assess the translational implications of cath L knockout in clinical settings. Ultimately, these findings may contribute to the development of novel treatment approaches for improving outcomes of RT in cancer patients.

The Significance of Cathepsin B in Mediating Radiation Resistance in Colon Carcinoma Cell Line (Caco-2).

Cathepsins (Caths) are lysosomal proteases that participate in various physiological and pathological processes. Accumulating evidence suggests that caths play a multifaceted role in cancer progression and radiotherapy resistance responses. Their proteolytic activity influences the tumor's response to radiation by affecting oxygenation, nutrient availability, and immune cell infiltration within the tumor microenvironment. Cathepsin-mediated DNA repair mechanisms can promote radioresistance in cancer cells, limiting the efficacy of radiotherapy. Additionally, caths have been associated with the activation of prosurvival signaling pathways, such as PI3K/Akt and NF-κB, which can confer resistance to radiation-induced cell death. However, the effectiveness of radiotherapy can be limited by intrinsic or acquired resistance mechanisms in cancer cells. In this study, the regulation and expression of cathepsin B (cath B) in the colon carcinoma cell line (caco-2) before and after exposure to radiation were investigated. Cells were exposed to escalating ionizing radiation doses (2 Gy, 4 Gy, 6 Gy, 8 Gy, and 10 Gy). Analysis of protein expression, in vitro labeling using activity-based probes DCG04, and cath B pull-down revealed a radiation-induced up-regulation of cathepsin B in a dose-independent manner. Proteolytic inhibition of cathepsin B by cathepsin B specific inhibitor CA074 has increased the cytotoxic effect and cell death due to ionizing irradiation treatment in caco-2 cells. Similar results were also obtained after cathepsin B knockout by CRISPR CAS9. Furthermore, upon exposure to radiation treatment, the inhibition of cath B led to a significant upregulation in the expression of the proapoptotic protein BAX, while it induced a significant reduction in the expression of the antiapoptotic protein BCL-2. These results showed that cathepsin B could contribute to ionizing radiation resistance, and the abolishment of cathepsin B, either by inhibition of its proteolytic activity or expression, has increased the caco-2 cells susceptibility to ionizing irradiation.

IAEA/WHO postal dosimetry audit methodology for electron beams using radio photoluminescent dosimeters.

BACKGROUND: Independent dosimetry audits are an important intervention in radiotherapy for quality assurance. Electron beams, used for superficial radiotherapy treatments, must also be tested in dosimetry audits as part of a good quality assurance program to help prevent clinical errors. PURPOSE: To establish a new service for IAEA/WHO postal dosimetry audits in electron beams using RPL dosimeters. METHODS: A novel postal audit methodology employing a PMMA holder system for RPLDs was developed. The associated correction factors including holder dependence, energy dependence, dose response non-linearity, and fading were obtained and tested in a multi-center (n = 12) pilot study. A measurement uncertainty budget was estimated and employed in analyzing the irradiated dosimeters. RESULTS: Holder and energy correction factors ranged from 1.004 to 1.010 and 1.019 to 1.059 respectively across the energy range. The non-linearity and fading correction models used for photon beams were tested in electron beams and did not significantly increase measurement uncertainty. The mean dose ratio ± SD of the multi-center study was 1.001 ± 0.011. The overall uncertainty budget was estimated as ± 1.42% (k = 1). CONCLUSIONS: A methodology for IAEA/WHO postal dosimetry audits in electron beams was developed and validated in a multi-center study and is now made available to radiotherapy centers as a routine service.

The role of SSDL in quality assurance in radiotherapy.

This paper describes the role of the Polish Secondary Standard Dosimetry Laboratory (SSDL) in quality assurance in radiotherapy by means of providing calibration of ionisation chambers, TLD postal dosimetry audits and end-to-end audits for radiation therapy. A historical review of the methods and results are presented. The influence of the SSDL in Warsaw on radiation protection of patients in Poland is discussed. The International Atomic Energy Agency together with World Health Organisation (IAEA/WHO), through its network of SSDLs around the world, propagates newly developed methods for calibration and auditing. Suitable high quality equipment was provided by the IAEA, as well as special materials and technical support to the SSDL in Warsaw. The activity of the SSDL and the services provided for Polish radiotherapy centres have resulted in a reduction of discrepancies between planned doses and doses delivered to patients. The newly tested IAEA methods of end-to-end on-site dosimetry audits allow for monitoring and improving the quality of IMRT in Poland. The traceability of standards used for the calibration of therapy level dosimeters from Polish radiotherapy centres is assured by the IAEA dosimetry laboratory. The consistency of methods performed in the Polish SSDL with the ISO:17025 norm is supervised by the Polish Centre for Accreditation - a member of International Laboratory Accreditation Cooperation (ILAC), for calibration and testing. Due to the rapid technological development of radiotherapy, special attention has to be paid to newly developed methods for dosimetry auditing and institutions which provide services for assuring radiation safety of patients.

Testing the methodology for a dosimetric end-to-end audit of IMRT/VMAT: results of IAEA multicentre and national studies.

Introduction: Within an International Atomic Energy Agency (IAEA) co-ordinated research project (CRP), a remote end-to-end dosimetric quality audit for intensity modulated radiation therapy (IMRT)/ volumetric arc therapy (VMAT) was developed to verify the radiotherapy chain including imaging, treatment planning and dose delivery. The methodology as well as the results obtained in a multicentre pilot study and national trial runs conducted in close cooperation with dosimetry audit networks (DANs) of IAEA Member States are presented.Material and methods: A solid polystyrene phantom containing a dosimetry insert with an irregular solid water planning target volume (PTV) and organ at risk (OAR) was designed for this audit. The insert can be preloaded with radiochromic film and four thermoluminescent dosimeters (TLDs). For the audit, radiotherapy centres were asked to scan the phantom, contour the structures, create an IMRT/VMAT treatment plan and irradiate the phantom. The dose prescription was to deliver 4 Gy to the PTV in two fractions and to limit the OAR dose to a maximum of 2.8 Gy. The TLD measured doses and film measured dose distributions were compared with the TPS calculations.Results: Sixteen hospitals from 13 countries and 64 hospitals from 6 countries participated in the multicenter pilot study and in the national runs, respectively. The TLD results for the PTV were all within ±5% acceptance limit for the multicentre pilot study, whereas for national runs, 17 participants failed to meet this criterion. All measured doses in the OAR were below the treatment planning constraint. The film analysis identified seven plans in national runs below the 90% passing rate gamma criteria.Conclusion: The results proved that the methodology of the IMRT/VMAT dosimetric end-to-end audit was feasible for its intended purpose, i.e., the phantom design and materials were suitable; the phantom was easy to use and it was robust enough for shipment. Most importantly the audit methodology was capable of identifying suboptimal IMRT/VMAT delivery.

A multi-centre analytical study of small field output factor calculations in radiotherapy.

An audit methodology was developed and applied for output factor (OF) calculations in radiotherapy. The auditees were asked to calculate OFs for field sizes from 10 × 10 cm2 to 2 × 2 cm2. Sixty five beams were audited; missing reference OFs were interpolated. The calculated OFs were in 73% of cases higher than the reference data. The smaller the field size, the higher the overestimations which were observed in the higher fraction of cases. Treatment planning systems generally overestimated OFs for small fields. The reference dataset helped radiotherapy centres to identify discrepancies which were higher than typical.

Tissue response after implantation of pure titanium and bioresorbable screws in scapula with postoperative irradiation: an experimental study on rats.

OBJECTIVE: The study focuses on the comparison of tissue reaction to titanium and bioresorbable implants with and without postoperative irradiation on an animal model. MATERIALS AND METHODS: Thirty-nine LEW/W rats were randomly assigned to experimental or control groups. One titanium and one bioresorbable screw (poly-L-lactide [PLLA] and L- and D-lactide poly-L/D-lactide [PDLLA]) were implanted into the left scapulas of 24 rats. Half of them received 30 Gy to the operation site and the other half received 42 Gy. In the control groups, 3 rats received 30 Gy, and 6 rats received 42 Gy to the scapula area without operation; and 6 rats had implants inserted as in the experimental group, but received no postoperative irradiation. The scapulas were removed 14 or 30 days after irradiation and a histologic analysis was performed. RESULTS: The host tissue reaction to titanium and PLLA-PDLLA screws without postoperative irradiation was of similar intensity. In irradiated animals, the inflammatory tissue reaction was more evident around the titanium screws than around the bioresorbable screws, irrespective of the radiation dose and of the time that elapsed from the irradiation. The reaction was more evident on the 14th day than on the 30th day after the last radiation dose (70 and 86 days after surgery, respectively). The intensity of the inflammatory tissue reaction, irrespective of the implant type, was more intense in the group irradiated with 42 Gy. CONCLUSIONS: PLLA-PDLLA implants appear to cause less tissue reaction after irradiation and could be safer reconstructive devices than titanium implants for patients undergoing surgery and adjuvant radiotherapy for cancer.

Long-term stability of radiotherapy dosimeters calibrated at the Polish Secondary Standard Dosimetry Laboratory.

Unidos 10001, Unidos E (10008/10009) and Dose 1 electrometers from 14 radiotherapy centres were calibrated 3-4 times over a long period of time, together with Farmer type (PTW 30001, 30013, Nuclear Enterprises 2571 and Scanditronix-Wellhofer FC65G) cylindrical ionization chambers and plane-parallel type chambers (PTW Markus 23343 and Scanditronix-Wellhofer PPC05). On the basis of the long period of repetitive establishing of calibration coefficients for the same electrometers and ionization chambers, the accuracy of electrometers and the long-term stability of ionization chambers were examined. All measurements were carried out at the same laboratory, by the same staff, according to the same IAEA recommendations. A good accuracy and long-term stability of the dosimeters used in Polish radiotherapy centres was observed. These values were within 0.1% for electrometers and 0.2% for the chambers with electrometers. Furthermore, these values were not observed to vary over time. The observations confirm the opinion that the requirement of calibration of the dosimeters more often than every 2 years is not justified.

Dosimetry audit of radiotherapy treatment planning systems.

In radiotherapy Treatment Planning Systems (TPS) various calculation algorithms are used. The accuracy of dose calculations has to be verified. Numerous phantom types, detectors and measurement methodologies are proposed to verify the TPS calculations with dosimetric measurements. A heterogeneous slab phantom has been designed within a Coordinated Research Project (CRP) of the IAEA. The heterogeneous phantom was developed in the frame of the IAEA CRP. The phantom consists of frame slabs made with polystyrene and exchangeable inhomogeneity slabs equivalent to bone or lung tissue. Special inserts allow to position thermoluminescent dosimeters (TLD) capsules within the polystyrene slabs below the bone or lung equivalent slabs and also within the lung equivalent material. Additionally, there are inserts that allow to position films or ionisation chamber in the phantom. Ten Polish radiotherapy centres (of 30 in total) were audited during on-site visits. Six different TPSs and five calculation algorithms were examined in the presence of inhomogeneities. Generally, most of the results from TLD were within 5 % tolerance. Differences between doses calculated by TPSs and measured with TLD did not exceed 4 % for bone and polystyrene equivalent materials. Under the lung equivalent material, on the beam axis the differences were lower than 5 %, whereas inside the lung equivalent material, off the beam axis, in some cases they were of around 7 %. The TLD results were confirmed with the ionisation chamber measurements. The comparison results of the calculations and the measurements allow to detect limitations of TPS calculation algorithms. The audits performed with the use of heterogeneous phantom and TLD seem to be an effective tool for detecting the limitations in the TPS performance or beam configuration errors at audited radiotherapy departments.

Dosimetric inter-institutional comparison in European radiotherapy centres: Results of IAEA supported treatment planning system audit.

BACKGROUND AND PURPOSE: One of the newer audit modalities operated by the International Atomic Energy Agency (IAEA) involves audits of treatment planning systems (TPS) in radiotherapy. The main focus of the audit is the dosimetry verification of the delivery of a radiation treatment plan for three-dimensional (3D) conformal radiotherapy using high energy photon beams. The audit has been carried out in eight European countries - Estonia, Hungary, Latvia, Lithuania, Serbia, Slovakia, Poland and Portugal. The corresponding results are presented. MATERIAL AND METHODS: The TPS audit reviews the dosimetry, treatment planning and radiotherapy delivery processes using the 'end-to-end' approach, i.e. following the pathway similar to that of the patient, through imaging, treatment planning and dose delivery. The audit is implemented at the national level with IAEA assistance. The national counterparts conduct the TPS audit at local radiotherapy centres through on-site visits. TPS calculated doses are compared with ion chamber measurements performed in an anthropomorphic phantom for eight test cases per algorithm/beam. A set of pre-defined agreement criteria is used to analyse the performance of TPSs. RESULTS: TPS audit was carried out in 60 radiotherapy centres. In total, 190 data sets (combination of algorithm and beam quality) have been collected and reviewed. Dosimetry problems requiring interventions were discovered in about 10% of datasets. In addition, suboptimal beam modelling in TPSs was discovered in a number of cases. CONCLUSIONS: The TPS audit project using the IAEA methodology has verified the treatment planning system calculations for 3D conformal radiotherapy in a group of radiotherapy centres in Europe. It contributed to achieving better understanding of the performance of TPSs and helped to resolve issues related to imaging, dosimetry and treatment planning.

Energy dependence of radiochromic dosimetry films for use in radiotherapy verification.

AIM: The purpose of the study was to examine the energy dependence of Gafchromic EBT radiochromic dosimetry films, in order to assess their potential use in intensity-modulated radiotherapy (IMRT) verifications. MATERIALS AND METHODS: The film samples were irradiated with doses from 0.1 to 12 Gy using photon beams from the energy range 1.25 MeV to 25 MV and the film response was measured using a flat-bed scanner. The samples were scanned and the film responses for different beam energies were compared. RESULTS: A high uncertainty in readout of the film response was observed for samples irradiated with doses lower than 1 Gy. The relative difference exceeds 20% for doses lower than 1 Gy while for doses over 1 Gy the measured film response differs by less than 5% for the whole examined energy range. The achieved uncertainty of the experimental procedure does not reveal any energy dependence of Gafchromic EBT film response in the investigated energy range. CONCLUSIONS: Gafchromic EBT film does not show any energy dependence in the conditions typical for IMRT but the doses measured for pre-treatment plan verifications should exceed 1 Gy.