Using the gamma-index analysis for inter-fractional comparison of in-beam PET images for head-and-neck treatment monitoring in proton therapy: A Monte Carlo simulation study.

GOAL: In-beam Positron Emission Tomography (PET) is a technique for in-vivo non-invasive treatment monitoring for proton therapy. To detect anatomical changes in patients with PET, various analysis methods exist, but their clinical interpretation is problematic. The goal of this work is to investigate whether the gamma-index analysis, widely used for dose comparisons, is an appropriate tool for comparing in-beam PET distributions. Focusing on a head-and-neck patient, we investigate whether the gamma-index map and the passing rate are sensitive to progressive anatomical changes. METHODS/MATERIALS: We simulated a treatment course of a proton therapy patient using FLUKA Monte Carlo simulations. Gradual emptying of the sinonasal cavity was modeled through a series of artificially modified CT scans. The in-beam PET activity distributions from three fields were evaluated, simulating a planar dual head geometry. We applied the 3D-gamma evaluation method to compare the PET images with a reference image without changes. Various tolerance criteria and parameters were tested, and results were compared to the CT-scans. RESULTS: Based on 210 MC simulations we identified appropriate parameters for the gamma-index analysis. Tolerance values of 3 mm/3% and 2 mm/2% were suited for comparison of simulated in-beam PET distributions. The gamma passing rate decreased with increasing volume change for all fields. CONCLUSION: The gamma-index analysis was found to be a useful tool for comparing simulated in-beam PET images, sensitive to sinonasal cavity emptying. Monitoring the gamma passing rate behavior over the treatment course is useful to detect anatomical changes occurring during the treatment course.

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO.

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan.

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: A voxel-based morphometry approach exploiting Monte Carlo simulations.

PURPOSE: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy-to-interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of treatment. METHODS: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the voxel-based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. RESULTS: The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. CONCLUSIONS: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments.

Monitoring Carbon Ion Beams Transverse Position Detecting Charged Secondary Fragments: Results From Patient Treatment Performed at CNAO.

Particle therapy in which deep seated tumours are treated using 12C ions (Carbon Ions RadioTherapy or CIRT) exploits the high conformity in the dose release, the high relative biological effectiveness and low oxygen enhancement ratio of such projectiles. The advantages of CIRT are driving a rapid increase in the number of centres that are trying to implement such technique. To fully profit from the ballistic precision achievable in delivering the dose to the target volume an online range verification system would be needed, but currently missing. The 12C ions beams range could only be monitored by looking at the secondary radiation emitted by the primary beam interaction with the patient tissues and no technical solution capable of the needed precision has been adopted in the clinical centres yet. The detection of charged secondary fragments, mainly protons, emitted by the patient is a promising approach, and is currently being explored in clinical trials at CNAO. Charged particles are easy to detect and can be back-tracked to the emission point with high efficiency in an almost background-free environment. These fragments are the product of projectiles fragmentation, and are hence mainly produced along the beam path inside the patient. This experimental signature can be used to monitor the beam position in the plane orthogonal to its flight direction, providing an online feedback to the beam transverse position monitor chambers used in the clinical centres. This information could be used to cross-check, validate and calibrate, whenever needed, the information provided by the ion chambers already implemented in most clinical centres as beam control detectors. In this paper we study the feasibility of such strategy in the clinical routine, analysing the data collected during the clinical trial performed at the CNAO facility on patients treated using 12C ions and monitored using the Dose Profiler (DP) detector developed within the INSIDE project. On the basis of the data collected monitoring three patients, the technique potential and limitations will be discussed.

Deep Seated Tumour Treatments With Electrons of High Energy Delivered at FLASH Rates: The Example of Prostate Cancer.

Different therapies are adopted for the treatment of deep seated tumours in combination or as an alternative to surgical removal or chemotherapy: radiotherapy with photons (RT), particle therapy (PT) with protons or even heavier ions like 12C, are now available in clinical centres. In addition to these irradiation modalities, the use of Very High Energy Electron (VHEE) beams (100-200 MeV) has been suggested in the past, but the diffusion of that technique was delayed due to the needed space and budget, with respect to standard photon devices. These disadvantages were not paired by an increased therapeutic efficacy, at least when comparing to proton or carbon ion beams. In this contribution we investigate how recent developments in electron beam therapy could reshape the treatments of deep seated tumours. In this respect we carefully explored the application of VHEE beams to the prostate cancer, a well-known and studied example of deep seated tumour currently treated with high efficacy both using RT and PT. The VHEE Treatment Planning System was obtained by means of an accurate Monte Carlo (MC) simulation of the electrons interactions with the patient body. A simple model of the FLASH effect (healthy tissues sparing at ultra-high dose rates), has been introduced and the results have been compared with conventional RT. The study demonstrates that VHEE beams, even in absence of a significant FLASH effect and with a reduced energy range (70-130 MeV) with respect to implementations already explored in literature, could be a good alternative to standard RT, even in the framework of technological developments that are nowadays affordable.

Addendum: Measurement of charged particle yields from PMMA irradiated by a 220 MeV/u 12C beam.

In this paper we report the re-analysis of the data published in (Piersanti et al. 2014) documenting the charged secondary particles production induced by the interaction of a 220 MeV/u 12C ion beam impinging on a polymethyl methacrylate (PMMA) target, measured in 2012 at the GSI facility in Darmstadt (Germany). This re-analysis takes into account the inhomogeneous light response of the LYSO crystal in the experimental setup measured in a subsequent experiment (2014) performed in the Heidelberg Ion- Beam Therapy Center. A better description of the detector and re-calculation of the geometrical efficiencies have been implemented as well, based on an improved approach that accounts also for the energy dependence of the emission spectrum. The new analysis has small effect on the total secondary charged flux, but has an impact on the production yield and emission velocity distributions of the different particle species (protons, deuterons and tritons) at different angles with respect to the beam direction (60° and 90°). All these observables indeed depend on the particle identification algorithms and hence on the LYSO detector energy response. The results of the data re-analysis presented here are intended to supersede and replace the results published in (Piersanti et al. 2014).

A Monte Carlo approach to the microdosimetric kinetic model to account for dose rate time structure effects in ion beam therapy with application in treatment planning simulations.

PURPOSE: Advanced ion beam therapeutic techniques, such as hypofractionation, respiratory gating, or laser-based pulsed beams, have dose rate time structures which are substantially different from those found in conventional approaches. The biological impact of the time structure is mediated through the ß parameter in the linear quadratic (LQ) model. The aim of this study was to assess the impact of changes in the value of the ß parameter on the treatment outcomes, also accounting for noninstantaneous intrafraction dose delivery or fractionation and comparing the effects of using different primary ions. METHODS: An original formulation of the microdosimetric kinetic model (MKM) is used (named MCt-MKM), in which a Monte Carlo (MC) approach was introduced to account for the stochastic spatio-temporal correlations characteristic of the irradiations and the cellular repair kinetics. A modified version of the kinetic equations, validated on experimental cell survival in vitro data, was also introduced. The model, trained on the HSG cells, was used to evaluate the relative biological effectiveness (RBE) for treatments with acute and protracted fractions. Exemplary cases of prostate cancer irradiated with different ion beams were evaluated to assess the impact of the temporal effects. RESULTS: The LQ parameters for a range of cell lines (V79, HSG, and T1) and ion species (H, He, C, and Ne) were evaluated and compared with the experimental data available in the literature, with good results. Notably, in contrast to the original MKM formulation, the MCt-MKM explicitly predicts an ion and LET-dependent ß compatible with observations. The data from a split-dose experiment were used to experimentally determine the value of the parameter related to the cellular repair kinetics. Concerning the clinical case considered, an RBE decrease was observed, depending on the dose, ion, and LET, exceeding up to 3% of the acute value in the case of a protraction in the delivery of 10 min. The intercomparison between different ions shows that the clinical optimality is strongly dependent on a complex interplay between the different physical and biological quantities considered. CONCLUSIONS: The present study provides a framework for exploiting the temporal effects of dose delivery. The results show the possibility of optimizing the treatment outcomes accounting for the correlation between the specific dose rate time structure and the spatial characteristic of the LET distribution, depending on the ion type used.

Design of a new tracking device for on-line beam range monitor in carbon therapy.

Charged particle therapy is a technique for cancer treatment that exploits hadron beams, mostly protons and carbon ions. A critical issue is the monitoring of the beam range so to check the correct dose deposition to the tumor and surrounding tissues. The design of a new tracking device for beam range real-time monitoring in pencil beam carbon ion therapy is presented. The proposed device tracks secondary charged particles produced by beam interactions in the patient tissue and exploits the correlation of the charged particle emission profile with the spatial dose deposition and the Bragg peak position. The detector, currently under construction, uses the information provided by 12 layers of scintillating fibers followed by a plastic scintillator and a pixelated Lutetium Fine Silicate (LFS) crystal calorimeter. An algorithm to account and correct for emission profile distortion due to charged secondaries absorption inside the patient tissue is also proposed. Finally detector reconstruction efficiency for charged particle emission profile is evaluated using a Monte Carlo simulation considering a quasi-realistic case of a non-homogenous phantom.

Monitoring of Hadrontherapy Treatments by Means of Charged Particle Detection.

The interaction of the incoming beam radiation with the patient body in hadrontherapy treatments produces secondary charged and neutral particles, whose detection can be used for monitoring purposes and to perform an on-line check of beam particle range. In the context of ion-therapy with active scanning, charged particles are potentially attractive since they can be easily tracked with a high efficiency, in presence of a relatively low background contamination. In order to verify the possibility of exploiting this approach for in-beam monitoring in ion-therapy, and to guide the design of specific detectors, both simulations and experimental tests are being performed with ion beams impinging on simple homogeneous tissue-like targets (PMMA). From these studies, a resolution of the order of few millimeters on the single track has been proven to be sufficient to exploit charged particle tracking for monitoring purposes, preserving the precision achievable on longitudinal shape. The results obtained so far show that the measurement of charged particles can be successfully implemented in a technology capable of monitoring both the dose profile and the position of the Bragg peak inside the target and finally lead to the design of a novel profile detector. Crucial aspects to be considered are the detector positioning, to be optimized in order to maximize the available statistics, and the capability of accounting for the multiple scattering interactions undergone by the charged fragments along their exit path from the patient body. The experimental results collected up to now are also valuable for the validation of Monte Carlo simulation software tools and their implementation in Treatment Planning Software packages.

The pharmacological costs of complete liver resections in unselected advanced colorectal cancer patients: a review of published Phase II and III trials.

The pharmacological costs of regimens used as front-line therapy in advanced colorectal cancer patients and their impact on the liver resection rates have not been considered. In this paper, we made a review of published randomized Phase II and III trials that reported the liver resection rates following upfront chemotherapy and linked this outcome to the pharmacological costs of drugs used. The costs are calculated based on the price at Pharmacy of our Hospital in Legnago (Italy), and as a measure of activity, we used the number of patients needed to treat to get one complete liver resection. Number needed to treat is highly variable among the different trials according to patient's characteristics, tumor biology and the efficacy of chemotherapy administered. The range of activity is greatly amplified when the costs are compared.

Atividade preemptiva da infiltração da incisão com ropivacaína a 0,75%, em pacientes submetidos à herniorrafia inguinal / Preemptive activity of incision infiltration with 0.75% ropivacaine in patients submitted to inguinal hernia repair

JUSTIFICATIVA E OBJETIVOS: A eficiência da analgesia preemptiva em relação ao regime convencional no controle da dor pós-operatória continua a ser controversa. O objetivo deste estudo foi avaliar a eficácia da infiltração local com ropivacaína a 0,75% antes e depois da incisão em operações de herniorrafia inguinal na intensidade da dor pós-operatória, no consumo de analgésicos e no tempo para solicitação da primeira dose de analgésico.MÉTODO: Após a aprovação pelo Comitê de Ética em Pesquisa Institucional, 60 pacientes, estado físico P1 ou P2, com idade entre 15 e 65 anos, submetidos à herniorrafia inguinal sob anestesia geral com isoflurano e fentanil foram distribuídos aleatoriamente em três grupos: A - infiltração da pele, subcutâneo e tecido muscular antes da incisão com 2 mg/kg de ropivacaína a 0,75%; D - infiltração da pele, subcutâneo e tecido muscular após incisão com 2 mg/kg de ropivacaína a 0,75%; e o C - grupo controle - sem infiltração. Todos os pacientes receberam dipirona (2 g), 30 minutos antes do final da anestesia. Uma bomba de analgesia controlada pelo paciente com morfina foi usada depois da recuperação da anestesia. Foram avaliados durante 24 horas a intensidade da dor com a escala analógica visual, o consumo total de morfina e o tempo para a solicitação da primeira dose de morfina. RESULTADOS: O consumo de morfina foi significativamente menor no grupo A (1,5 mg) quando comparado ao grupo D de (5,5 mg) ou controle (17 mg). O tempo para a solicitação da primeira dose de morfina foi significativamente maior para o grupo A assim como a intensidade da dor em todos os momentos quando comparado ao grupo C e nas últimas 18 h comparado ao grupo.CONCLUSÃO: A infiltração pré-operatória da incisão com ropivacaína reduz significativamente a intensidade da dor e o consumo de morfina pós-operatória e retarda o tempo para a solicitação da primeira dose de morfina.

BACKGROUND AND OBJECTIVES: The effectiveness of preemptive analgesia as compared to the conventional regimen for postoperative pain control is still controversial. This study aimed at evaluating the effectiveness of local infiltration with 0.75% ropivacaine before and after the incision of inguinal hernia repair surgeries in postoperative pain intensity, analgesics consumption and time elapsed for first analgesic dose request. METHOD: After the Institutional Research Ethics Committee approval, 60 patients, physical status P1 or P2, aged between 15 and 65 years, submitted to inguinal hernia repair under general anesthesia with isoflurane and fentanyl were randomly distributed in three groups: A - skin, subcutaneous and muscle infiltration before incision with 2 mg/kg of 0.75% ropivacaine; D - skin, subcutaneous and muscle infiltration after incision with 2 mg/kg of 0.75% ropivacaine; and C - control group, without infiltration. All patients received dipirone (2 g), 30 minutes before the end of anesthesia.A patient-controlled analgesia pump with morphine was used after anesthetic recovery. Pain intensity with visual analog scale, total morphine consumption and time for the first morphine dose request were evaluated during 24 hours.RESULTS: Morphine consumption was significantly lower in the A group (1.5 mg) as compared to the D group (5.5 mg) or to the control group (17 mg). Time for first morphine dose request was significantly longer for the A group and pain intensity was lower in all moments as compared to C group and in the last 18 h as compared to the group.CONCLUSION: Preoperative incision infiltration with ropivacaine significantly decreases postoperative pain intensity and morphine consumption and delays the time for first morphine dose request.

Evaluation of ketorolac compared to ketorolacplus dipyrone in post-operative analgesiaof videolaparoscopic cholecystectomy / Avaliação do efeito da dipirona associada ao cetorolaco comparado ao cetorolaco em pós-operatório de colecistectomia videolaparoscópica

Objectives: To compare the analgesic effect of ketorolac with the association of ketorolac plus dipyrone after videolaparoscpic cholecystectomy and with a placebo group. Methods: After approval by the Research Ethics Committee and after having the informed consent signed, 60 patients aged between 18 and 60 years who underwent videolaparoscopic cholecystectomy were evaluated for the post-operative analgesia provided by ketorolac compared to ketorolac plus dipyrone. The patients underwent general anesthesia (with propofol, alfentanil, rocuronium and maintenance with isoflurane). Twenty patients received 20 ml water, 20 patients received ketorolac 30 mg in 20 ml water and 20 received ketorolac 30 mg plus dipyrone 2 g in 20 ml water, during anesthetic induction. In the post-operative recovery room, the patients were evaluated to the moment of their first pain complaint with the use of a visual analogue scale and a verbal pain scale every hour in the first six hours. When necessary, morphine was administered as a rescue medication for pain relief and a PCA pump with morphine solution was turned on. Results: Total morphine use was lower in the ketorolac plus dipyrone Group (2 mg) and in the ketorolac (2 mg) Group, compared to the placebo Group (10.5 mg). Of 20 cases of ketorolac plus dipyrone, eight patients did not complain of pain in the post-operative period, while only three patients did not complain in the ketorolac Group and in the placebo Group (p = 0,05). Conclusion: Ketorolac is a potent analgesic agent widely used for acute pain treatment, especially after surgeries, with an analgesic potency comparable to that of opiates, the most commonly drugs used during the post-operative of medium to major surgeries. In this study, the results analyzed at this moment show that the association of ketorolac plus dipyrone seemed to be superior to post-operative analgesia compared to the use of ketorolac.

Objetivos: Comparar o efeito analgésico do cetorolaco e da associação cetorolaco mais dipirona após cirurgias de colecistectomias videolaparoscópicas. Métodos: Após a aprovação do Comitê de Ética e a obtenção do consentimento informado, 60 pacientes com idade entre 18 a 60 anos e candidatos à colecistectomia videolaparoscópica, foram submetidos ao procedimento cirúrgico sob anestesia geral balanceada com propofol, alfentanil, rocurônio e manutenção com isoflurano. Foram divididos em três grupos: placebo, recebendo 20 ml de solução salina; cetorolaco com 30 mg de cetorolaco em 20 ml de solução salina; e cetorolaco mais dipirona, recebendo 30 mg de cetorolaco e 2 g de dipirona em 20 ml de solução salina. Os fármacos foram aplicados por via venosa, no início da incisão cirúrgica. Na sala de recuperação pós-anestésica os pacientes foram avaliados, quanto ao momento da primeira queixa dolorosa pela escala visual analógica e verbal e grau de sedação, a cada hora nas primeiras seis horas. Se necessário era utilizada como medicação de resgate, morfina administrada por bomba de analgesia controlada pelo paciente. Resultados: O consumo total de morfina no pós-operatório foi menor no Grupo cetorolaco mais dipirona (2 mg) e no Grupo cetorolaco (2 mg) comparado ao Grupo placebo (10,5 mg) com p = 0,10. No Grupo cetorolaco mais dipirona, oito pacientes não referiram dor no pós-operatório, enquanto que apenas três no Grupo cetorolaco e três no Grupo placebo não se queixaram de dor (p = 0,05, teste do χ2). Conclusão: O cetorolaco tem sido amplamente utilizado no tratamento da dor aguda, especialmente a pós-operatória, principalmente em cirurgias de médio e grande porte, isoladas ou associadas aos opioides. No presente estudo, a associação de cetorolaco com dipirona se mostrou superior na analgesia após colecistectomias videolaparoscópicas quando comparada ao cetorolaco.