Physics and Imaging in Radiation Oncology 15 (2020) 108–116 Contents lists available at ScienceDirect Physics and Imaging in Radiation Oncology journal homepage: www.elsevier.com/locate/phro Review Article In vivo dosimetry in external beam photon radiotherapy: Requirements and T future directions for research, development, and clinical practice☆ Igor Olaciregui-Ruiza, , Sam Beddarb, Peter Greerc, Nuria Jornetd, Boyd McCurdye, ⁎ Gabriel Paiva-Fonsecaf, Ben Mijnheera, Frank Verhaegenf a Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands b Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA c Calvary Mater Newcastle Hospital and University of Newcastle, Newcastle, New South Wales, Australia d Servei de Radiofísica i Radioprotecció, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain e Medical Physics Department, CancerCare Manitoba, Winnipeg, Manitoba, Canada f Department of Radiation Oncology (Maastro), GROW School for Oncology, Maastricht University Medical Centre+, Maastricht, the Netherlands ARTICLE INFO ABSTRACT Keywords: External beam radiotherapy with photon beams is a highly accurate treatment modality, but requires extensive In vivo dosimetry quality assurance programs to confirm that radiation therapy will be or was administered appropriately. In vivo External beam radiotherapy dosimetry (IVD) is an essential element of modern radiation therapy because it provides the ability to catch Electronic portal imaging device treatment delivery errors, assist in treatment adaptation, and record the actual dose delivered to the patient. Task group report However, for various reasons, its clinical implementation has been slow and limited. The purpose of this report is Review to stimulate the wider use of IVD for external beam radiotherapy, and in particular of systems using electronic portal imaging devices (EPIDs). After documenting the current IVD methods, this report provides detailed software, hardware and system requirements for in vivo EPID dosimetry systems in order to help in bridging the current vendor-user gap. The report also outlines directions for further development and research. In vivo EPID dosimetry vendors, in collaboration with users across multiple institutions, are requested to improve the un­ derstanding and reduce the uncertainties of the system and to help in the determination of optimal action limits for error detection. Finally, the report recommends that automation of all aspects of IVD is needed to help facilitate clinical adoption, including automation of image acquisition, analysis, result interpretation, and re­ porting/documentation. With the guidance of this report, it is hoped that widespread clinical use of IVD will be significantly accelerated. 1. Introduction Therefore, one would expect that IVD is already an essential link in the clinical workflow of modern radiotherapy. However, very few radio­ External beam radiotherapy (EBRT) with photon beams has seen therapy centers perform IVD during beam delivery [2]. The current major progress in recent decades in the form of treatment planning, standard is to perform dosimetry checks using pretreatment dose beam delivery, and image guidance. Nonetheless, despite best efforts, measurements in phantoms, which requires major resources but cannot the actual delivered dose to the patient can differ from the planned catch errors related to patient geometry or in beam delivery during the dose. Among the many reasons for this are inaccuracies in the calcu­ actual treatment [3]. lations of treatment planning systems (TPSs), errors in plan transfer to The purpose of this report is to analyze why IVD currently is not the accelerator or in beam delivery, and differences in patient geometry routinely performed, which methods are available, which methods need between the planning and treatment stages. The three aims of in vivo more development, and what needs to be done to augment clinical dosimetry (IVD) [1] are to catch treatment errors, assist in treatment acceptance of the various methods. Although IVD is a widely applied adaptation, and record the actual dose delivered to the patient. term, its use easily causes misunderstandings not only between vendors ☆ During the 1st ESTRO Physics Workshop celebrated in November 2017 in Glasgow, Scotland, a task group was created to stimulate the wider adoption of in vivo dosimetry for external beam photon radiotherapy. The members of this task group, authors of this report, were selected on the basis of their expertise to contribute relevant input to the area of study and their long-term experience in the clinical implementation of in vivo dosimetry systems. ⁎ Corresponding author at: Department of Radiation Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. E-mail address: i.olaciregui@nki.nl (I. Olaciregui-Ruiz). https://doi.org/10.1016/j.phro.2020.08.003 Received 26 March 2020; Received in revised form 17 August 2020; Accepted 18 August 2020 Available online 29 August 2020 2405-6316/ © 2020 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). I. Olaciregui-Ruiz, et al. Physics and Imaging in Radiation Oncology 15 (2020) 108–116 and users but also within the research community. In order to prevent report covers the main concepts and defines a basic terminology for the future misinterpretations, a concise definition of IVD in the scope of current types of EIVD systems. This terminology is used to guide readers EBRT is provided in the Methods section. According to this definition, through the next sections. point detectors placed on the patient’s skin in the treatment field such The report identifies a list of system, software, hardware and user as thermoluminescent detectors, silicon diodes, metal-oxide semi­ requirements needed for the widespread clinical implementation of conductor field-effect transistors, optically stimulated luminescence EIVD systems. Requirements are presented for the overall EIVD system, dosimeters, and electronic portal imaging devices (EPIDs) [4,5] are the as well as for the different subsystems: EPID imager, image acquisition main commercially available IVD methods. Due to the limitations of software and EIVD software. Specific requirements for automation are point detectors for large-scale implementation of IVD in modern EBRT, also provided as they are key to guarantee an optimal balance between the emphasis of this report lies on EPID-based IVD (EIVD) systems. resources and performance. The requirements list was elaborated first EPIDs are nowadays ubiquitous on modern accelerators, they are easy by the members of the task group with experience implementing EIVD to use, they have potential for automation and they can perform dosi­ systems and then reviewed by the rest of the task group members fol­ metric verification in 2D or 3D. The use of EPIDs for dosimetric mea­ lowing an iterative process. Further recommendations are made for surements has matured for both pre-treatment patient-specific quality vendors and researchers in areas where improvements are needed for a assurance (QA) [6] and IVD [7–10]. The various EPID dosimetry ap­ wider clinical adoption of EIVD systems. proaches have been discussed in a comprehensive way in a review ar­ The references in the manuscript were selected to assist in the ticle by van Elmpt et al. [11], and have been discussed further in the narrative of the report either by providing evidence for particular updated literature review by McCurdy et al. [12]. Currently, commer­ statements or by pointing to extra sources for further technical details cial EPID dosimetry software products are available from several ven­ but are not needed to understand the text. The references were screened dors. While vendors generally provide specific guidelines and overall for their inclusion by all members of the task group first and later by the support for the implementation of their EIVD system, the user has an advisory group. important role in commissioning and implementation of these systems. However, there are currently no specific guidelines for users of EIVD 3. Current IVD methods systems on the potential, limitations and correct utilization of EIVD systems. 3.1. Point detectors This report identifies system, software, hardware and user require­ ments needed for the widespread clinical implementation of EIVD Many types of point dose detector systems are available for IVD. The systems. While mainly directed at vendors, these requirements should most commonly used are diodes, thermoluminescent dosimeters, and be of help in bridging the current vendor-user gap. To ensure a clear metal-oxidesemiconductor field-effect transistors. Optically stimulated understanding of these requirements, the main concepts and basic ter­ luminescent dosimeters and plastic scintillation detectors have recently minology for the current types of EIVD methods are introduced. Finally, come into use for IVD [13–19]. The use of detectors for IVD in EBRT further directions for development are proposed to vendors and re­ requires calibration methods to correlate the detector reading with the searchers in areas where improvements are needed for a wider adoption delivered dose [20,21]. Point detectors, either placed on the skin of the of EIVD systems. The report focuses on the use of EIVD systems for patient or embedded in the immobilization mask or frame, are typically common external photon beam technology. Other IVD systems are only used to measure entrance dose and/or exit dose. In conformal beam briefly discussed. radiotherapy, entrance IVD can detect major errors, mainly those caused by incorrect beam parameter settings (data transfer between 2. Methods and materials planning and delivery) or machine malfunctions [22]. Before the widespread use of record-and-verify systems and the automatic transfer 2.1. IVD definition of all beam parameters from the TPS to the treatment units, entrance IVD was shown to detect data transfer errors [23]. By combining en­ IVD is a radiation measurement that is acquired while the patient is being trance with exit measurements, differences in patient anatomy between treated containing information related to the absorbed dose in the patient. planning and delivery can also be detected [24]. However, the transi­ This definition implies that an IVD system must be able to capture errors due tion from simple conformal fields to intensity-modulated techniques to equipment failure, errors in dose calculation, patient positioning errors, such as intensity-modulated radiation therapy (IMRT) and volumetric and patient anatomy changes. modulated arc therapy (VMAT) has limited the usefulness of point The definition excludes all ‘transmission dosimetry’ methods that measurements [25,26], particularly when bearing in mind the addi­ capture only the accelerator exit dose/energy fluence (or related tional uncertainty due to placement error, which can substantially quantities or metrics) before the beam reaches the patient, even if these impact measured-to-planned dose agreement of point detectors in high are combined with a cone beam computed tomography (CBCT) image gradient regions, demonstrating the criticality of accurate dosimeter acquired right before treatment delivery. Using an accelerator log file, placement for IMRT and VMAT treatments [27]. even in combination with a CBCT image, is also not considered IVD. Point detectors that can be placed inside a catheter or implanted near The aforementioned systems can, however, complement IVD methods. the tumor can provide direct verification of the actual dose delivered to Also, the comparison of an EPID image made during a specific fraction the tumor or organ at risk [15,28,29]. The main limitation of these de­ of a patient treatment with a reference EPID image, e.g., of the first tectors for clinical implementation is their invasiveness. Even when pla­ fraction, may miss dose errors present in the reference image and is cement of the detector near the tumor is possible, the location of the therefore a constancy check but not in vivo dosimetry. While such detector, combined with changes in patient anatomy, means that the re­ methods can be valuable tools for patient-specific QA, they are cur­ sults may have large uncertainties. In addition, the dose can be checked at rently not categorized as IVD. only one or a few points. Finally, point detectors may perturb the dose. Point detectors are useful in determining skin dose and peripheral 2.2. Structure of task group report dose (e.g., contralateral breast, lens of eye, scrotum), as most TPSs do not provide accurate dose calculations in these situations. Point de­ While the emphasis of this report lies on EIVD systems, the report tectors can also confirm that cardiovascular implantable electronic presents first a brief state-of-the-art overview of the use of point de­ devices (e.g., pacemakers) receive a minimal dose (below the manu­ tectors where their future role and limitations are recognized. As was facturer’s specified dose limits) [30]. In the absence of TPSs, such as for the case with the definition of IVD, and to avoid misinterpretations, this total body irradiation or intraoperative radiation therapy, IVD with 109 I. Olaciregui-Ruiz, et al. Physics and Imaging in Radiation Oncology 15 (2020) 108–116 point detectors has proven to be valuable [31–34]. portal dose image. This method requires an algorithm to convert the Even if point detectors still have a role for 3D conformal beam measured signals to dose in water or measured portal dose image in­ radiotherapy, for skin and peripheral dose measurements, for special cluding corrections for energy-dependent response [56]. techniques, and for dosimetry audits for clinical trials [35], their lim­ Most implementations to date employ non-time-resolved methods itations of for large-scale implementation of IVD are obvious. First, using the integrated image signal; however, for VMAT, this obviously point dosimetry is insufficient for patient-specific QA in modern EBRT. has major limitations. Time-resolved analysis for VMAT deliveries can Point detectors are cumbersome and intrusive, add extra time to be performed following alignment of predicted and measured images treatment delivery, cannot be automated and require well-trained staff. [44,57]. Experience with an online system using comparison of pre­ Due to the recognized limitations of point detectors for a widespread dicted to measured portal images has been reported [51]. implementation of IVD, the focus of this report is on the use of EPID A disadvantage of these types of EIVD methods at the plane of the dosimetry for IVD. EPID is that the comparisons are not intuitive and cannot easily be related to clinically relevant comparison metrics such as patients’ dose 3.2. EPID dosimetry for IVD volume histograms. However, they do not contain any less information on the delivery than back-projection systems. Generally, 2D planar Although initially developed for patient setup verification, EPIDs show gamma analysis is employed, but other metrics have also been in­ also useful dosimetric characteristics [36–39] that have made them suitable vestigated [58]. for the implementation of IVD verification solutions [8,40–50]. Beginning in the early 2000 s, the current generation of amorphous-silicon flat-panel 3.2.2. Back-projection systems within the patient: dose reconstructed within EPID technology became commercially available from major linac manu­ a patient model facturers and today is a ubiquitous choice on newly purchased linacs. The These systems estimate a point dose or dose distribution within a primary layers of an amorphous silicon EPID detection structure are a patient model from the measured EPID image. When the patient model is buildup or interaction layer, which is usually copper; a scintillating phos­ a CBCT scan acquired immediately prior to treatment, then the dose is an phor layer, usually gadolinium oxysulfide; and the photo-diode matrix, estimate of the delivered dose for that treatment fraction as it accounts for whose support material is amorphous silicon. Owing to the high atomic the anatomy of the patient before the delivery [45,59]. When, as is more number (Z) of the materials and the inherent beam-energy spectrum, the common, the patient model is the planning CT scan, then the estimated response of the EPID will differ from ion-chamber measurements. Other dose in this model can be used to determine a change in the delivery from factors that modify the spectrum, such as patient attenuation, field size, off- the planned delivery. A recent paper studied the effect of the choice of axis distance, and patient-to-EPID distance, also contribute to this differ­ patient model on the performance of in vivo 3D EPID dosimetry [60]. In ence. All EIVD systems use the measured image signal from the transmis­ this paper, it was concluded that with planning CT images as patient sion energy fluence that impinges on the detector. This is affected by: (1) model, EPID dose reconstructions underestimate the dosimetric effects the incident beam fluence from the linac impinging on the patient, (2) caused by errors in patient positioning and overestimate the dosimetric primary fluence attenuation in the patient, (3) scatter from the patient, and effects caused by changes in patient anatomy. (4) the response of the EPID to (2) and (3). For direct back-projection systems the primary fluence at the plane of Typically, EIVD assessments are performed by combining the data of the EPID is usually derived by correction of EPID scatter and patient all EPID frames acquired during delivery. Time-resolved analysis refers scatter. This fluence is back-projected through the patient model and to assessments using subsets of frames or cumulative frame signals. combined with dose-deposition kernels to determine the dose dis­ These frames can be grouped according to time, control point, or gantry tribution [42,61]. Solutions have been presented to compensate the angle. Offline assessment is performed after delivery and can be per­ suboptimal support for density inhomogeneities in these simple dose formed using both time-resolved and non-time-resolved methods calculations [62,63]. Other empirically based approaches have been [7,44]. Online assessment is performed in real time using time-resolved developed to determine dose at a point or a plane in the patient model analysis so that assessment is made before the total dose has been de­ from the EPID image [64,65]. For indirect back-projection systems, the livered to the patient, with the aim to interrupt treatment [51,52]. primary fluence is back-projected through the patient model to de­ Supplementary Table S7 provides a brief overview of currently avail­ termine the incident fluence to the patient. This is then used with a able EIVD systems. These systems do not all comply with all of the conventional patient dose-calculation engine and analytical and Monte requirements formulated in this report. Carlo methods have been employed [47,66,67]. The clear advantages of back-projection systems are that the esti­ 3.2.1. Forward systems at the EPID level mated dose is more intuitive and that differences can be evaluated by A direct method of EIVD is to predict and compare the measured direct comparison to the planned dose distribution in the patient model portal image signals to a predicted portal image. This method uses the using gamma or dose volume histogram evaluations. The majority of treatment plan and planning CT with a physics model that typically implementations have been offline, although an online system has also includes an incident fluence model, a patient attenuation and scatter been reported [52]. For back-projection systems for VMAT, a time-re­ model, a treatment couch attenuation model, and an EPID energy de­ solved acquisition and back-projection method is required; however, position model. Monte Carlo and analytical techniques have been used the analysis is typically based on the integrated back-projected signal in this approach [46,53-55]. Another closely related method is to pre­ [43]. A brief overview of the currently available EIVD methods is dict the dose to a water slab at the position of the EPID, i.e., a predicted presented in Table 1. Table 1 Currently available types of EIVD systems. System type Comparison location Prediction Measured/EPID-reconstructed Forward systems (EPID) EPID plane Predicted portal image. Grayscale values. Measured portal image. Grayscale values. Forward systems (dose) EPID plane Predicted portal dose to water slab. Measured portal dose to water slab. Back-projection systems (direct) Within patient model Treatment planning system. Dose in Dose back-projection directly into patient model. patient model. Back-projection systems (indirect) Within patient model Treatment planning system. Dose in Dose back-projection through patient to incident fluence. Calculate patient model. dose in patient model. 110 I. Olaciregui-Ruiz, et al. Physics and Imaging in Radiation Oncology 15 (2020) 108–116 4. Requirements for EPID-based IVD systems workload, acceptance tests and acceptance criteria [71–73]. Regarding periodic QA procedures, the test frequency, equipment, expected Detailed software and hardware requirements regarding the overall workload and automatic possibilities must also be known. system performance, as well as EPID imager, MV image acquisition software and IVD software are presented as Supplementary Material, see Tables S1–S4. 5. Future directions for research, development and clinical Furthermore, for a successful large-scale implementation, EIVD practice systems must ensure a manageable and configurable workload to guarantee an optimal balance between resources and performance 5.1. Uncertainties [7,8,48,68]. Automation is essential for large-scale clinical im­ plementation of EIVD systems because it reduces the number of labor- IVD systems need to assess whether the actual dose delivered to the intensive, time-consuming, and error-prone tasks [69,70]. Automation patient DD lies within agreed-upon dosimetric lower and higher toler­ also allows for more frequent use of the system, e.g., for all fractions. ance limit values (TL, TH) with respect to the originally intended See Supplementary Table S5 for the specific list of requirements on the planned dose value DP [74]. In this assessment, the measured in vivo automation steps. In case automation is only partly available, the whole dose value DIVD is used for an estimation of DD. The uncertainty UIVD in verification process must be carefully described, and an estimation of the DIVD measurement defines the range of values (and their prob­ the workload required to perform the non-automated tasks must be ability) within which DD is expected to lie. The probability density provided. Note that full automation is a requisite for online assess­ function of delivered dose values PDFDD is used to calculate the like­ ments. lihood that the delivered dose deviation will exceed the tolerance limit In an automated environment, the inspection of alerts becomes the values (see Fig. 2) and needs to be taken into account when defining only remaining work. Vendors are expected to facilitate a streamlined dosimetric action limits for IVD systems. Note that for EIVD, the workspace for the timely inspection of alerts (Requirements S5.7 and meaning of ‘dose’ differs among systems, and ‘value’ is often not a point S5.8) and additional tools to aid in the alert inspection work dose value but a 2D/3D dose distribution. (S4.13–15). An estimate of the average per-treatment alert-manage­ EIVD vendors, possibly in collaboration with users across multiple ment workload must also be given. Fig. 1 displays a flow chart illus­ institutions utilizing different technologies, should put efforts into de­ trating the basics of an EIVD alert-inspection workflow. termining UIVD for all dose comparison indicators and clinically re­ The commissioning of the EIVD system also demands resources and levant combinations of delivery techniques and treatment disease sites, manpower. Vendors are expected to provide information about the see Requirement S1.13. The determination can be made by comparing commissioning equipment and the measurement procedures, expected DIVD dose values against reference values that can be reasonably used as DD or by simply considering the inherent spread of DIVD dose values in Fig. 1. Basics of an EIVD alert-inspection workflow. 111 I. Olaciregui-Ruiz, et al. Physics and Imaging in Radiation Oncology 15 (2020) 108–116 Fig. 2. Probability density functions of delivered dose values corresponding to two DIVD measure­ ments, one inside (IVDin) and one outside (IVDout) the dosimetric tolerance limit values (DP − TL, DP + TH). The graph illustrates how the uncertainty of the IVD system influences the likelihood that the actual delivered dose deviation will exceed the tolerance limits (gray shaded areas). For simplicity, UIVD is assumed to follow a normal distribution without bias. nominally “error-free” deliveries. It may be insightful to evaluate the False positives lead to unnecessary extra inspection work, while false uncertainty of the system for increasing levels of complexity: (i) simple negatives hide errors not detected by the system. The reasons for in­ plans, e.g. square fields, on homogeneous phantoms, (ii) complex plans correct classification are EIVD uncertainties, EIVD limitations and the on homogeneous phantoms and (iii) complex plans on anthro­ inappropriate choice of action limits. pomorphic phantoms. In addition, extra uncertainties in case of un­ Ultimately, the error detectability of an IVD system is expressed in corrected errors in patient positioning and/or anatomy changes if daily terms of its sensitivity and specificity, i.e., the true positive rate and patient imaging is not used in the reconstruction should be evaluated. true negative rate, respectively. EIVD vendors are requested to help the The presence of a bias in UIVD distributions would suggest that there user community determine the sensitivity and specificity of the system is a systematic error in the determination of DIVD dose values that needs for a set of representative clinical situations, for instance through large- to be corrected. scale trials and information gathering initiatives. This includes an as­ Furthermore, EIVD vendors need to explain the main causes for sessment of the dependency on treatment site, delivery technique, and/ uncertainty and put efforts into not only assessing but also reducing the or indicator used. These studies would help in determining optimal uncertainty. action limits to detect errors of a given magnitude and in elucidating the possibilities and limitations of the IVD system, e.g., situations where 5.2. Error detection clinically relevant deviations do not significantly change the recorded signal at the EPID level. The ultimate goal of IVD is error detection, i.e., to detect deviations Receiver operating characteristic (ROC) curves can be used to between planned dose distributions and delivered dose values ex­ evaluate the ability of IVD systems to correctly classify observed dose ceeding specified tolerance limits. An overview with the errors that deviations and to determine optimal action limits [77]. ROC analysis, EIVD systems are expected to detect is presented as Supplementary however, requires a statistically significant size of error and no-error Material, see Table S6. The detectability of a specific type of error de­ samples as input. The experimental acquisition of EPID measurements pends very much on the specificity and sensitivity of a particular EIVD to produce such samples is typically a cumbersome process, which ex­ system for that type of error, as discussed in the next section. Mijnheer plains why there are only a few studies on the topic in the IVD literature [75] presented an overview of the different types of errors detected by [78–81]. Recently, use has been made of synthetic EPID images to various groups using both in-house-developed and commercial EIVD eliminate the need for phantom error introduction and positioning systems. In this overview, examples of point-dose errors, errors in the [82]. Another alternative is to model possible errors by introducing 2D or 3D features of leaf sequencing, dose calculation errors, and pa­ modifications in the TPS [83]. Vendors, in collaboration with the tient-related errors are shown. Bojechko et al. [76] analyzed a series of clinical community, are requested to promote research activities related near-miss incidents with high potential severity at their institute. Most to the error detectability of their IVD systems and to facilitate colla­ of these errors cannot be detected by means of pretreatment dose ver­ boration within a user group. Additional research is also required to ification, highlighting the importance of IVD. investigate the use of alternative measurement analysis techniques, e.g., use of exploratory data analysis, radiomics, and/or machine learning 5.3. Specificity and sensitivity [84–86]. IVD systems act as binary classifiers where treatments are identified 5.4. Online systems either as positive (alerted) or negative (not alerted). Ideally, a treat­ ment should be classified as a positive only if the actual delivered dose Online EIVD is performed in real time using time-resolved analysis deviation is relevant to the outcome of the treatment; and otherwise it with the aim to interrupt treatment before the total dose has been de­ should be considered a negative. In practice, however, treatments are livered to the patient [51,52]. There are additional challenges with sometimes incorrectly identified: e.g., non-relevant dose deviations online EIVD systems such as speed, latency, robustness, specificity, and classified as positives or relevant dose deviations classified as negatives. tolerances for real-time analysis that require further research. 112 I. Olaciregui-Ruiz, et al. Physics and Imaging in Radiation Oncology 15 (2020) 108–116 5.5. EPID technology delivered dose or the beam range have been proposed and in some cases already clinically investigated [105]. For these EBRT systems new The main limitation of the use of standard amorphous-silicon EPID techniques for IVD should be developed. technology for in vivo dosimetry is the non-water-equivalent response which demands extra commissioning steps and software corrections to 6. Discussion effectively model the dose response characteristics of the EPID imager [87,88]. Although research efforts have been made to modify current This report has documented IVD methods used in EBRT, focusing on EPID designs to make them more water-equivalent [89–92], none of EPID-based approaches. The report provides detailed requirements to these configurations have been adopted for clinical use yet. One of the vendors for overall EIVD system performance, as well as for the EPID reasons is that EPID technology developments over recent decades have imager, image acquisition software, and IVD analysis software. Further not been driven by the demands of IVD, but by the needs for improved recommendations are made for vendors and researchers to improve the patient positioning. understanding and reduce the uncertainties in IVD systems and to es­ timate the sensitivity and specificity of the system. Finally, the report 5.6. Other IVD systems recommends that automation of all aspects of EIVD is needed to help facilitate clinical adoption, including automation of image acquisition, In this section, several new developments of IVD in radiotherapy are analysis, result interpretation, and reporting/documentation. discussed using systems other than EIVD. These systems need further In some cases, requirements are stated without any numerical spe­ investigation before they can be used with the required accuracy. cifications. This is because specific tolerance values for some of the The use of Gafchromic film for in vivo entrance dose determination criteria will depend on the application. A few of these requirements are can be advantageous compared to point detectors if a higher resolution elementary and are being satisfied by today’s technology, while others is needed. Gafchromic film can furthermore be used to determine the are not available yet. The goal of this report is to raise awareness for the skin dose when introducing a new treatment technique or during total need of each of the proposed requirements and to prompt users of EIVD skin electron therapy. Several studies have also shown the usefulness of systems to ask vendors for details about their fulfilment, using quanti­ Gafchromic film during intraoperative radiotherapy, both with electron tative information whenever applicable. An essential requirement that beams and with low-energy X-ray beams [93]. Improvements regarding has been identified for the seamless integration of the different sub­ film reading characteristics are still needed to increase the accuracy of systems is the use of open, free and non-proprietary formats and in­ dose measurements for these types of IVD measurements. terfaces, e.g. Requirement S3.11. The fulfilment of this requirement PRESAGE, which is an optically transparent radiochromic dosi­ would simplify the implementation of EIVD systems and would allow meter, has a comparable resolution to Gafchromic film. PRESAGE researchers to gain easy access to EPID data in their studies. Another sheets have the same dosimetric capability as Gafchromic film but are example would be Requirement S3.8 where it is stated that “each in­ softer and more flexible to conform to the patient’s skin, which makes tegrated image and each cine mode image frame must be tagged with them in principle a valuable tool for IVD [94,95]. However, currently real-time treatment delivery information”. But in order to achieve this, there is only limited experience with PRESAGE sheets. linac manufacturers must provide an open interface for access to the Recently, Cherenkov imaging has been shown to allow high-re­ raw portal image data and related real-time information which would solution, video-rate imaging of radiation delivery to tissue using a gated be beneficial to both potential new vendors of MV acquisition software camera system. The Cherenkov emission can be used to evaluate the and researchers. surface dose received by the patient in real time. However, the re­ Task Group 307 (TG307) has been recently formed by the American lationship between the video signal and the actual in vivo dose is Association of Physicists in Medicine (AAPM) to review the use of EPIDs complex. Cherenkov radiation emission in radiotherapy is affected by for Patient-Specific IMRT and VMAT QA. This task group aims to pro­ tissue optical properties (e.g., pigmentation, thickness of tissue), en­ vide an extensive review on existing EPID products, methods and al­ trance/exit geometry, and imaging angles. Despite the limitations of gorithms for both pre-treatment and in vivo dosimetric verification. It is Cherenkov imaging, several interesting applications have been re­ hoped that the proposed requirements in this EBRT IVD report will not ported. These include in vivo surface dose measurements during total only complement the ongoing TG307 work, but will also contribute to skin electron therapy [96] and imaging during breast treatments to raise the awareness of the community about the required capabilities of monitor beam shape in real time on the patient’s skin throughout the EIVD systems and inspire further related work. For example, it may lead treatment [97]. to recommendations for a set of customer acceptance tests to evaluate Recent in vivo investigations have shown that short pulses of ra­ and compare the basic performance of EIVD systems to detect errors. diation at very-high-dose rates (several hundred Gy/s) are less harmful In practice, and owing to the presence of false positives and false to healthy tissue but just as efficient as conventional dose-rate radiation negatives, EIVD systems are typically implemented in combination with at inhibiting tumor growth. A first patient treatment using this so-called other patient-specific QA systems. False negatives are of particular FLASH effect has recently been described [98]. IVD during FLASH importance because they hide relevant errors that are not being de­ radiotherapy is strongly recommended due to the uncertainties in beam tected [82]. To detect these errors, EIVD must be used in combination calibration and beam monitoring. It seems, therefore, worthwhile to with image-guided radiation therapy procedures such as CBCT visua­ investigate whether existing IVD detectors can be used for this purpose lization and/or CBCT-based dose calculations. Similarly, the use of linac after determination of their dosimetric characteristics in very-high- log files or transmission detectors mounted on the linac head may show dose-rate fields [99–101]. additional value in the detection of, or confirmation of the absence of, IVD should also be accepted as an essential part of translational and machine delivery errors. Other QA systems, such as 2D/3D detector preclinical research, where the dose uncertainties are often large [102]. matrices or independent dose calculations, can help to discriminate The potential use of EIVD systems in a similar way to that used during between false and true positives during the inspection of EIVD alerts patient EBRT treatments has been reported for the verification of small (see Fig. 2). Table S8 lists several commercial systems that may com­ animal kilovoltage X-ray irradiations [103,104], but this needs further plement EIVD methods. Finally, note that the sensitivity and specificity investigation. of EIVD highly conditions the feasibility of clinical workflows. For in­ Finally, it should be noted that there are several EBRT systems stance, if a specific EIVD system is very sensitive to changes in patient where IVD is not used such as the Cyberknife, Tomotherapy, Gamma anatomy for a specific treatment site, then EIVD assessments could be Knife and ViewRay MR-linac. Also in proton therapy IVD is not used used to trigger the acquisition of CBCTs in case that these are not ac­ routinely, although various techniques for in vivo verification of the quired daily. 113 I. Olaciregui-Ruiz, et al. Physics and Imaging in Radiation Oncology 15 (2020) 108–116 One aspect that has received little or no attention so far is auditing [10] McCurdy BMC, McCowan PM. 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Real-time in vivo rectal wall dosimetry using plastic scintillation detectors for patients with prostate cancer. Phys Med Biol 2014;59:647–60. https://doi.org/10.1088/0031-9155/59/3/647. The authors declare the following financial interests/personal re­ [16] Jornet N, Carrasco P, Jurado D, Ruiz A, Eudaldo T, Ribas M. Comparison study of lationships which may be considered as potential competing interests: I MOSFET detectors and diodes for entrance in vivo dosimetry in 18 MV x-ray Olaciregui-Ruiz and B Mijnheer declare that their department licensed beams. Med Phys 2004;31:2534–42. https://doi.org/10.1118/1.1785452. [17] Beaulieu L, Beddar S. Review of plastic and liquid scintillation dosimetry for portal dosimetry software to Elekta Oncology Systems Ltd. for the de­ photon, electron, and proton therapy. Phys Med Biol 2016;61:R305–43. https:// velopment of the iViewDose product. This product is currently not doi.org/10.1088/0031-9155/61/20/R305. commercially available. 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