Guido Pedroli

APPLICATION OF FAILURE MODE AND EFFECTS ANALYSIS TO INTRAOPERATIVE RADIATION THERAPY USING MOBILE ELECTRON LINEAR ACCELERATORS

PURPOSE Failure mode and effects analysis (FMEA) represents a prospective approach for risk assessment. A multidisciplinary working group of the Italian Association for Medical Physics applied FMEA to electron beam intraoperative radiation therapy (IORT) delivered using mobile linear accelerators, aiming at preventing accidental exposures to the patient. METHODS AND MATERIALS FMEA was applied to the IORT process, for the stages of the treatment delivery and verification, and consisted of three steps: 1) identification of the involved subprocesses; 2) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system, based on the product of three parameters (severity, frequency of occurrence and detectability, each ranging from 1 to 10); 3) identification of additional safety measures to be proposed for process quality and safety improvement. RPN upper threshold for little concern of risk was set at 125. RESULTS Twenty-four subprocesses were identified. Ten potential failure modes were found and scored, in terms of RPN, in the range of 42-216. The most critical failure modes consisted of internal shield misalignment, wrong Monitor Unit calculation and incorrect data entry at treatment console. Potential causes of failure included shield displacement, human errors, such as underestimation of CTV extension, mainly because of lack of adequate training and time pressures, failure in the communication between operators, and machine malfunctioning. The main effects of failure were represented by CTV underdose, wrong dose distribution and/or delivery, unintended normal tissue irradiation. As additional safety measures, the utilization of a dedicated staff for IORT, double-checking of MU calculation and data entry and finally implementation of in vivo dosimetry were suggested. CONCLUSIONS FMEA appeared as a useful tool for prospective evaluation of patient safety in radiotherapy. The application of this method to IORT lead to identify three safety measures for risk mitigation.

Calculation of electron and isotopes dose point kernels with fluka Monte Carlo code for dosimetry in nuclear medicine therapy

PURPOSE The calculation of patient-specific dose distribution can be achieved by Monte Carlo simulations or by analytical methods. In this study, FLUKA Monte Carlo code has been considered for use in nuclear medicine dosimetry. Up to now, FLUKA has mainly been dedicated to other fields, namely high energy physics, radiation protection, and hadrontherapy. When first employing a Monte Carlo code for nuclear medicine dosimetry, its results concerning electron transport at energies typical of nuclear medicine applications need to be verified. This is commonly achieved by means of calculation of a representative parameter and comparison with reference data. Dose point kernel (DPK), quantifying the energy deposition all around a point isotropic source, is often the one. METHODS FLUKA DPKS have been calculated in both water and compact bone for monoenergetic electrons (10-3 MeV) and for beta emitting isotopes commonly used for therapy (89Sr, 90Y, 131I 153Sm, 177Lu, 186Re, and 188Re). Point isotropic sources have been simulated at the center of a water (bone) sphere, and deposed energy has been tallied in concentric shells. FLUKA outcomes have been compared to PENELOPE v.2008 results, calculated in this study as well. Moreover, in case of monoenergetic electrons in water, comparison with the data from the literature (ETRAN, GEANT4, MCNPX) has been done. Maximum percentage differences within 0.8.RCSDA and 0.9.RCSDA for monoenergetic electrons (RCSDA being the continuous slowing down approximation range) and within 0.8.X90 and 0.9.X90 for isotopes (X90 being the radius of the sphere in which 90% of the emitted energy is absorbed) have been computed, together with the average percentage difference within 0.9.RCSDA and 0.9.X90 for electrons and isotopes, respectively. RESULTS Concerning monoenergetic electrons, within 0.8.RCSDA (where 90%-97% of the particle energy is deposed), FLUKA and PENELOPE agree mostly within 7%, except for 10 and 20 keV electrons (12% in water, 8.3% in bone). The discrepancies between FLUKA and the other codes are of the same order of magnitude than those observed when comparing the other codes among them, which can be referred to the different simulation algorithms. When considering the beta spectra, discrepancies notably reduce: within 0.9.X90, FLUKA and PENELOPE differ for less than 1% in water and less than 2% in bone with any of the isotopes here considered. Complete data of FLUKA DPKS are given as Supplementary Material as a tool to perform dosimetry by analytical point kernel convolution. CONCLUSIONS FLUKA provides reliable results when transporting electrons in the low energy range, proving to be an adequate tool for nuclear medicine dosimetry.

Use of machine learning methods for prediction of acute toxicity in organs at risk following prostate radiotherapy

PURPOSE The goal of this study is to investigate the advantages of large scale optimization methods vs conventional classification techniques in predicting acute toxicity for urinary bladder and rectum due to prostate irradiation. METHODS Clinical and dosimetric data of 321 patients undergoing prostate conformal radiotherapy were recorded. Gastro-intestinal and genito-urinary acute toxicities were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale. Patients were classified in two categories to separate mild (Grade < 2) from severe toxicity levels (Grade > 2). Machine learning methods at different complexity were implemented to predict toxicity as a function of multiple variables. The first approach consisted of a large scale optimization method, based on genetic algorithms (GAs) and artificial neural networks (ANN). The second approach was a binary classifier based on support vector machines (SVM). RESULTS The ANN and SVM-based solutions showed comparable prediction accuracy, exhibiting an area under the receiver operating characteristic (ROC) curve of 0.7. Different sensitivity and specificity features were measured for the two approaches. The ANN algorithm showed enhanced sensitivity if combined with appropriate classification criteria. CONCLUSIONS The results demonstrate that high sensitivity in toxicity prediction can be achieved with optimized ANNs, that are put forward to represent a valuable support in medical decisions. Future studies will be focused on enlarging the available patient database to increase the reliability of toxicity prediction algorithms and to define optimal classification criteria.

Use of the FLUKA Monte Carlo code for 3D patient-specific dosimetry on PET-CT and SPECT-CT images

Patient-specific absorbed dose calculation for nuclear medicine therapy is a topic of increasing interest. 3D dosimetry at the voxel level is one of the major improvements for the development of more accurate calculation techniques, as compared to the standard dosimetry at the organ level. This study aims to use the FLUKA Monte Carlo code to perform patient-specific 3D dosimetry through direct Monte Carlo simulation on PET-CT and SPECT-CT images. To this aim, dedicated routines were developed in the FLUKA environment. Two sets of simulations were performed on model and phantom images. Firstly, the correct handling of PET and SPECT images was tested under the assumption of homogeneous water medium by comparing FLUKA results with those obtained with the voxel kernel convolution method and with other Monte Carlo-based tools developed to the same purpose (the EGS-based 3D-RD software and the MCNP5-based MCID). Afterwards, the correct integration of the PET/SPECT and CT information was tested, performing direct simulations on PET/CT images for both homogeneous (water) and non-homogeneous (water with air, lung and bone inserts) phantoms. Comparison was performed with the other Monte Carlo tools performing direct simulation as well. The absorbed dose maps were compared at the voxel level. In the case of homogeneous water, by simulating 10(8) primary particles a 2% average difference with respect to the kernel convolution method was achieved; such difference was lower than the statistical uncertainty affecting the FLUKA results. The agreement with the other tools was within 3–4%, partially ascribable to the differences among the simulation algorithms. Including the CT-based density map, the average difference was always within 4% irrespective of the medium (water, air, bone), except for a maximum 6% value when comparing FLUKA and 3D-RD in air. The results confirmed that the routines were properly developed, opening the way for the use of FLUKA for patient-specific, image-based dosimetry in nuclear medicine.

First ex vivo validation of a radioguided surgery technique with β-radiation

PURPOSE A radio-guided surgery technique with β(-)-emitting radio-tracers was suggested to overcome the effect of the large penetration of γ radiation. The feasibility studies in the case of brain tumors and abdominal neuro-endocrine tumors were based on simulations starting from PET images with several underlying assumptions. This paper reports, as proof-of-principle of this technique, an ex vivo test on a meningioma patient. This test allowed to validate the whole chain, from the evaluation of the SUV of the tumor, to the assumptions on the bio-distribution and the signal detection. METHODS A patient affected by meningioma was administered 300MBq of (90)Y-DOTATOC. Several samples extracted from the meningioma and the nearby Dura Mater were analyzed with a β(-) probe designed specifically for this radio-guided surgery technique. The observed signals were compared both with the evaluation from the histology and with the Monte Carlo simulation. RESULTS we obtained a large signal on the bulk tumor (105cps) and a significant signal on residuals of ∼0.2ml (28cps). We also show that simulations predict correctly the observed yields and this allows us to estimate that the healthy tissues would return negligible signals (≈1cps). This test also demonstrated that the exposure of the medical staff is negligible and that among the biological wastes only urine has a significant activity. CONCLUSIONS This proof-of-principle test on a patient assessed that the technique is feasible with negligible background to medical personnel and confirmed that the expectations obtained with Monte Carlo simulations starting from diagnostic PET images are correct.

Physical and clinical implications of radiotherapy treatment of prostate cancer using a full bladder protocol

PurposeTo assess the dosimetric and clinical implication when applying the full bladder protocol for the treatment of the localized prostate cancer (PCA).Patients and MethodsA total of 26 consecutive patients were selected for the present study. Patients underwent two series of CT scans: the day of the simulation and after 40 Gy. Each series consisted of two consecutive scans: (1) full bladder (FB) and (2) empty bladder (EB). The contouring of clinical target volumes (CTVs) and organs at risk (OAR) were compared to evaluate organ motion. Treatment plans were compared by dose distribution and dose–volume histograms (DVH).ResultsCTV shifts were negligible in the laterolateral and superior–inferior directions (the maximum shift was 1.85 mm). Larger shifts were recorded in the anterior–posterior direction (95% CI, 0.83–4.41 mm). From the dosimetric point of view, shifts are negligible: the minimum dose to the CTV was 98.5% (median; 95%CI, 95–99%). The potential advantage for GU toxicity in applying the FB treatment protocol was measured: the ratio between full and empty bladder dose–volume points (selected from our protocol) is below 0.61, excluding the higher dose region where DVHs converge.ConclusionHaving a FB during radiotherapy does not affect treatment effectiveness, on the contrary it helps achieve a more favorable DVH and lower GU toxicities.ZusammenfassungZielEvaluierung der dosimetrischen und klinischen Implikationen bei Anwendung des Gefüllte-Blase-(FB-)Protokolls für die Behandlung des lokalisierten Prostatakarzinoms (PCA).Patienten und Methoden26 Patienten wurden für die vorliegende Studie ausgewählt. Sie unterzogen sich zwei Serien von CT-Scans: am Tag der Simulation und nach der Strahlendosis von 40 Gy. Jede Serie bestand aus zwei aufeinanderfolgenden Scans: mit gefüllter (FB) und mit leerer Blase (EB). Die Konturierung der CTVs und OARs wurden verglichen, um die Organbewegung abzuschätzen. Die Behandlungspläne wurden hinsichtlich Dosis und DVH verglichen.ErgebnisseDie CTV-Verschiebungen waren vernachlässigbar in laterolateraler und superior-inferiorer Richtung (maximale Verschiebung: 1,85 mm). Größere Verschiebungen wurden in anterior-posteriorer Richtung dokumentiert (0,83–4,41 mm; 95%-CI). In dosimetrischer Hinsicht sind die Verschiebungen geringfügig: Die minimale CTV-Dosis lag bei 98,5% (95– 99%, Median, 95% -CI). Der potentielle Vorteil hinsichtlich der GU-Toxizität bei Anwendung des FB-Behandlungsprotokolls war messbar: Das Verhältnis der Dosis-Volumen-Punkte (aus unserem Protokoll) bei gefüllter bzw. leerer Blase lag unter 0,61, mit Ausnahme der höheren Dosisbereiche, wo die DVHs konvergieren.SchlussfolgerungFB während der Strahlentherapie hat keinen Einfluss auf die Wirksamkeit der Behandlung, bewirkt jedoch günstigere DVHs und niedrigere GU-Toxizität.

Physikalische und klinische Implikationen der Behandlung bei gefüllter Blase in der Strahlentherapie des Prostatakarzinoms

PurposeTo assess the dosimetric and clinical implication when applying the full bladder protocol for the treatment of the localized prostate cancer (PCA).Patients and MethodsA total of 26 consecutive patients were selected for the present study. Patients underwent two series of CT scans: the day of the simulation and after 40 Gy. Each series consisted of two consecutive scans: (1) full bladder (FB) and (2) empty bladder (EB). The contouring of clinical target volumes (CTVs) and organs at risk (OAR) were compared to evaluate organ motion. Treatment plans were compared by dose distribution and dose–volume histograms (DVH).ResultsCTV shifts were negligible in the laterolateral and superior–inferior directions (the maximum shift was 1.85 mm). Larger shifts were recorded in the anterior–posterior direction (95% CI, 0.83–4.41 mm). From the dosimetric point of view, shifts are negligible: the minimum dose to the CTV was 98.5% (median; 95%CI, 95–99%). The potential advantage for GU toxicity in applying the FB treatment protocol was measured: the ratio between full and empty bladder dose–volume points (selected from our protocol) is below 0.61, excluding the higher dose region where DVHs converge.ConclusionHaving a FB during radiotherapy does not affect treatment effectiveness, on the contrary it helps achieve a more favorable DVH and lower GU toxicities.ZusammenfassungZielEvaluierung der dosimetrischen und klinischen Implikationen bei Anwendung des Gefüllte-Blase-(FB-)Protokolls für die Behandlung des lokalisierten Prostatakarzinoms (PCA).Patienten und Methoden26 Patienten wurden für die vorliegende Studie ausgewählt. Sie unterzogen sich zwei Serien von CT-Scans: am Tag der Simulation und nach der Strahlendosis von 40 Gy. Jede Serie bestand aus zwei aufeinanderfolgenden Scans: mit gefüllter (FB) und mit leerer Blase (EB). Die Konturierung der CTVs und OARs wurden verglichen, um die Organbewegung abzuschätzen. Die Behandlungspläne wurden hinsichtlich Dosis und DVH verglichen.ErgebnisseDie CTV-Verschiebungen waren vernachlässigbar in laterolateraler und superior-inferiorer Richtung (maximale Verschiebung: 1,85 mm). Größere Verschiebungen wurden in anterior-posteriorer Richtung dokumentiert (0,83–4,41 mm; 95%-CI). In dosimetrischer Hinsicht sind die Verschiebungen geringfügig: Die minimale CTV-Dosis lag bei 98,5% (95– 99%, Median, 95% -CI). Der potentielle Vorteil hinsichtlich der GU-Toxizität bei Anwendung des FB-Behandlungsprotokolls war messbar: Das Verhältnis der Dosis-Volumen-Punkte (aus unserem Protokoll) bei gefüllter bzw. leerer Blase lag unter 0,61, mit Ausnahme der höheren Dosisbereiche, wo die DVHs konvergieren.SchlussfolgerungFB während der Strahlentherapie hat keinen Einfluss auf die Wirksamkeit der Behandlung, bewirkt jedoch günstigere DVHs und niedrigere GU-Toxizität.

Radiation survey around a Liac mobile electron linear accelerator for intraoperative radiation therapy

The aim of this study was to perform a detailed analysis of the air kerma values around a Liac mobile linear accelerator working in a conventional operating room (OR) for IORT. The Liac delivers electron beams at 4, 6, 8 and 10 MeV. A radiation survey to determine photon leakage and scatter consisted of air kerma measurements on a spherical surface of 1.5 m radius, centered on the titanium exit window of the accelerating structure. Measurements were taken using a 30 cm3 calibrated cylindrical ion chamber in three orthogonal planes, at the maximum electron energy. For each point, 10 Gy was delivered. At selected points, the quality of x‐ray radiation was determined by using lead sheets, and measurements were performed for all energies to investigate the energy dependence of stray radiation. The photon scatter contribution from the metallic internal patient‐shielding in IORT, used to protect normal tissues underlying the target, was also evaluated. At seven locations outside the OR, the air kerma values derived from in‐room measurements were compared to measurements directly performed using a survey meter. The results, for a delivered dose of 10 Gy, showed that the air kerma values ranged from approximately 6 μGy (upper and rear sides of the Liac) to 320 μGy (lateral to beam stopper) in the two orthogonal vertical planes, while values lower than 18 μGy were found in the horizontal plane. At 10 MeV, transmission behind 1 cm lead shield was found to be 42%. The use of internal shielding appeared to increase the photon scatter only slightly. Air kerma values outside the OR were generally lower than 1 mGy for an annual workload of 200 patients. Thus, the Liac can safely work in a conventional OR, while the need for additional shielding mainly depends on patient workload. Our data can be useful for centers planning to implement an IORT program using a mobile linear accelerator, permitting radiation safety personnel to estimate in advance the shielding required for a particular workload. PACS number: 87.55.ne, 87.56.bd

Planning Combined Treatments of External Beam Radiation Therapy and Molecular Radiotherapy

Molecular radiotherapy (MRT) with radiolabeled molecules has being constantly evolving, leading to notable results in cancer treatment. In some cases, the absorbed doses delivered to tumors by MRT are sufficient to obtain complete responses; in other cases, instead, to be effective, MRT needs to be combined with other therapeutic approaches. Recently, several studies proposed the combination of MRT with external beam radiation therapy (EBRT). Some describe the theoretical basis within radiobiological models, others report the results of clinical phase I-II studies aimed to assess the feasibility and tolerability. The latter includes the treatment of various tumors, such as meningiomas, paragangliomas, non-Hodgkins lymphomas, bone, brain, hepatic, and breast lesions. The underlying principle of combined MRT and EBRT is the possibility of exploiting the full potential of each modality, given the different organs at risk. Target tissues can indeed receive a higher irradiation, while respecting the threshold limits of more than one critical tissue. Nevertheless, clinical trials are empirical and optimization is still a theoretical issue. This article describes the state of the art of combined MRT and EBRT regarding the rationale and the results of clinical studies, with special focus on the possibility of treatment improvement.

Dosimetry for Beta-Emitter Radionuclides by Means of Monte Carlo Simulations

Nowadays, there are interests as well as active investigations devoted to the study and application of radiolabeled molecules able to selectively target and irradiate tumoral cells during nuclear medicine procedures. With this kind of pharmaceuticals, spatial activity distribution with extremely non-uniform characteristics may be assessed in patients. Actually, this feature constitutes precisely themain advantage in view ofmaximizing the discrimination between affected and healthy tissue. The mentioned situation constitutes the main motivation for the present work. In this sense, the chapter is focused on nuclear medicine dosimetry pointing out the main features about how to implement Monte Carlo (MC) approaches to this aim. Nowadays, from a general point of view, therapies with radiopharmaceuticals using beta-emitter radionuclides are growing significantly and very fast. Beta-emitters can be emitters of β− or β+ radiation. Commonly, β+ emitters, like 18F are used for imaging techniques, whereas β− are mainly used with therapeutic purposes, to deliver high dose rate on tumors. Therefore, β− emitters are usually those of more interest for dosimetry. During nuclear medicine procedures, radiopharmaceutical activity distribution may be determined by means of different modalities. Nowadays it is mainly assessed using imaging techniques but otherwise it is also possible to infer it [Stabin (2008)]. This information is then incorporated in the treatment planning system in order to obtain an estimation of the dose distribution. More specifically, patient-specific dose distribution owing to alpha, beta and/or gamma emitters can be calculated starting from activity distribution by means of either direct MC simulation or analytical methods. On the other hand, patient-specific dosimetry requires anatomical information, which shall be further considered as input for establishing mass distribution during MC computations. Patient anatomical information can be suitably extracted from typical non-invasive imaging techniques, like computed tomography (CT) or magnetic resonance imaging (MRI). Many studies have been performed by means of MC applications in Nuclear Medicine up today, both in the imaging field, and regarding dosimetry calculations [F. Botta & Valente (2011), Zubal & Harrel (1992), H. Yoriyaz & dos Santos (2001), M. Ljungberg & Strand (2002)]. I troduction 11