Unraveling the impact of upfront chemotherapy and proton beam therapy on treatment outcome and follow-up in central nervous system germ cell tumors: a single center experience.

Background: Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. Materials and methods: We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Results: Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Conclusions: Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

Acute Hematological Toxicity during Cranio-Spinal Proton Therapy in Pediatric Brain Embryonal Tumors.

BACKGROUND: Embryonal tumors represent a heterogeneous entity of brain tumors that need a multidisciplinary treatment including cranio-spinal irradiation (CSI), with a known impact on the acute toxicity. Proton therapy (PT) boasts a reduction in acute hematological toxicity. METHODS: We retrospectively examined 20 pediatric patients affected by high-risk medulloblastoma and other rare embryonal brain tumors subjected to CSI with PT from September 2016 to April 2020. Before CSI, all patients received induction chemotherapy, and three patients additionally received two high-dose courses with thiotepa, followed by an autologous haemopoietic stem cell transplantation. We recorded the total white blood cell count, absolute neutrophil count, platelets, and hemoglobin levels for all patients during PT. RESULTS: Leucocytes and neutrophils decreased directly after the beginning of treatment, reaching a complete recovery at the end of treatment. Hemoglobin values remained constant over the treatment course. The median platelet value decreased until reaching a plateau around halfway through therapy, followed by a slow increase. No cases of febrile neutropenia or severe infections were reported. No treatment discontinuation due to hematological toxicity was necessary. CONCLUSIONS: CSI with PT was proven to be safe in this setting of pediatric patients. Our study showed that despite all patients having undergone chemotherapy prior to irradiation, no serious hematological toxicity was reported at the end of the treatment with PT, and, therefore, no treatment was discontinued or delayed.

Technical challenges in the treatment of mediastinal lymphomas by proton pencil beam scanning and deep inspiration breath-hold.

PURPOSE: To comprehensively describe the treatment of mediastinal lymphoma by pencil beam scanning (PBS) proton therapy. METHODS: Fourteen patients underwent PBS proton treatment in a supine position in deep inspiration breath-hold (DIBH). Three DIBH computed tomography (CT) scans were acquired for each patient to delineate the Internal Target Volume (ITV). Intensity-modulated proton therapy (IMPT) was planned by min-max robust optimization on the ITV, with a 6 mm setup and 3.5% range uncertainties. Robustness analysis was performed and dose coverage was visually inspected on the corresponding voxel-wise minimum map. Layer repainting was set equal to 5 to compensate for cardiac motion. Intra-fraction reproducibility during treatment was assessed by repeated daily DIBH X-ray imaging. Finally, an additional CT was acquired at half treatment to estimate the impact of inter-fraction dosimetric reproducibility. RESULTS: IMPT guaranteed robust mediastinal target coverage and organs-at-risk sparing. However, visual voxel-wise robustness evaluation showed that in five patients a second optimization with focused objectives in the cost-function was necessary to achieve a robust coverage of the target regions at the interface between lungs and soft tissue. In six patients, repainting was not used due to excessive treatment time length and poor patient compliance. Intra-fraction average reproducibility was within 1 mm/1degree. On repeated CT scans, inter-fraction setup errors and/or anatomical changes showed minimal dosimetric differences in CTV coverage. CONCLUSION: IMPT in DIBH is effective and reproducible to treat mediastinal lymphomas. Caution is recommended to guarantee robust dose delivery to high-risk regions at the interface between lungs and soft tissue.

Magnetic Resonance Imaging during Proton Therapy Irradiation Allows for the Early Response Assessment of Pediatric Chordoma.

Chordoma in pediatric patients is very rare. Proton therapy has become a gold standard in the treatment of these neoplasms, as high dose escalation can be achieved regarding the target while maximizing the sparing of the healthy tissues near the tumor. The aim of the work was to assess the evolution of morphological sequences during treatment using T1/T2-weighted magnetic resonance imaging (MRI) for the early response assessment of a classic chordoma of the skull base in a pediatric patient who had undergone surgical excision. Our results demonstrated a significant quantitative reduction in the residual nodule component adhered to the medullary bulb junction, with an almost complete recovery of normal anatomy at the end of the irradiation treatment. This was mainly shown in the T2-weighted MRI. On the other hand, the classic component of the lesion was predominantly present and located around the tooth of the axis. The occipital condyles were morphologically and dimensionally stable for the entire irradiation period. In conclusion, the application of this type of monitoring methodology, which is unusual during the administration of a proton treatment for chordoma, highlighted the unexpected early response of the disease. At the same time, it allowed the continuous assessment of the reliability of the treatment plan.

Clinical validation of a GPU-based Monte Carlo dose engine of a commercial treatment planning system for pencil beam scanning proton therapy.

PURPOSE: To perform the validation of the GPU-based (Graphical Processing Unit based) proton Monte Carlo (MC) dose engine implemented in a commercial TPS (RayStation 10B) and to report final dose calculation times for clinical cases. MATERIALS AND METHODS: 440 patients treated at the Proton Therapy Center of Trento, Italy, between 2018 and 2019 were selected for this study. 636 approved plans with 3361 beams computed with the clinically implemented CPU-MC dose engine (version 4.2 and 4.5), were used for the validation of the new algorithm. For each beam, the dose was recalculated using the new GPU-MC dose engine with the initial CPU computation settings and compared to the original CPU-MC dose. Beam dose difference distributions were studied to ensure that the two dose distributions were equal within the expected fluctuations of the MC statistical uncertainty (s) of each computation. Plan dose distributions were compared with respect to the dosimetric indices D98, D50 and D1 of all ROIs defined as targets. A complete assessment of the computation time as a function of s and dose grid voxel size was done. RESULTS: The median over all mean beam dose differences between CPU- and GPU-MC was -0.01% and the median of the corresponding standard deviations was close to (√2s) both for simulations with an s of 0.5% and 1.0% per beam. This shows that the two dose distributions can be considered equal. All the DVH indices showed an average difference below 0.04%. About half of the plans were computed with 1.0% statistical uncertainty on a 2 mm dose calculation grid, for which the median computation time was 5.2 s. The median computational speed for all plans in the study was 8.4 million protons/second. CONCLUSION: A validation of a clinical MC algorithm running on GPU was performed on a large pool of patients treated with pencil beam scanning proton therapy. We demonstrated that the differences with the previous CPU-based MC were only due to the intrinsic statistical fluctuations of the MC method, which translated to insignificant differences on plan dose level. The significant increase in dose calculation speed is expected to facilitate new clinical workflows.

Results of an independent dosimetry audit for scanned proton beam therapy facilities.

PURPOSE: An independent dosimetry audit based on end-to-end testing of the entire chain of radiation therapy delivery is highly recommended to ensure consistent treatments among proton therapy centers. This study presents an auditing methodology developed by the MedAustron Ion Beam Therapy Center (Austria) in collaboration with the National Physical Laboratory (UK) and audit results for five scanned proton beam therapy facilities in Europe. METHODS: The audit procedure used a homogeneous and an anthropomorphic head phantom. The phantoms were loaded either with an ionization chamber or with alanine pellets and radiochromic films. Homogeneously planned doses of 10Gy were delivered to a box-like target volume in the homogeneous phantom and to two clinical scenarios with increasing complexity in the head phantom. RESULTS: For all tests the mean of the local differences of the absolute dose to water determined with the alanine pellets compared to the predicted dose from the treatment planning system installed at the audited institution was determined. The mean value taken over all tests performed was -0.1±1.0%. The measurements carried out with the ionization chamber were consistent with the dose determined by the alanine pellets with a mean deviation of -0.5±0.6%. CONCLUSION: The developed dosimetry audit method was successfully applied at five proton centers including various "turn-key" Cyclotron solutions by IBA, Varian and Mevion. This independent audit with extension to other tumour sites and use of the correspondent anthropomorphic phantoms may be proposed as part of a credentialing procedure for future clinical trials in proton beam therapy.

Correction of the measured current of a small-gap plane-parallel ionization chamber in proton beams in the presence of charge multiplication.

PURPOSE: The aims of this work are to study the response of a small-gap plane-parallel ionization chamber in the presence of charge multiplication and suggest an experimental method to determine the product of the recombination correction factor (ks) and the charge multiplication correction factor (kCM) in order to investigate the latter. METHODS: Experimental data were acquired in scanned proton beams and in a Cobalt-60 beam. Measurements were carried out using an IBA PPC05 chambers of which the electrode gap is 0.6mm. The study is based on the determination of Jaffé plots by operating the chambers at different voltages. Experimental results are compared to theoretical equations describing initial and volume recombination as well as charge multiplication for continuous and pulsed beams. RESULTS: Results obtained in protons and Cobalt-60 with the same PPC05 chamber indicate that the charge multiplication effect is independent of the beam quality, while results obtained in different proton beams with two different PPC05 chambers show that the charge multiplication effect is chamber dependent. CONCLUSIONS: The approach to be taken when using a small-gap plane-parallel ionization chamber with a high voltage (e.g. 300V or 500V) for reference dosimetry in scanned proton beams depends on which correction factors were applied to the chamber response during its calibration in terms of absorbed dose to water: In both cases, it is recommended to use the ionization chamber at the same operating voltage used during its ND,w-calibration. Another solution consists of operating the PPC05 chamber at a lower voltage (e.g. 50V) with larger ks and smaller kCM and determining the product of both factors with higher accuracy using a linear extrapolation method.

Longitudinal Changes in Brain Diffusion MRI Indices during and after Proton Beam Therapy in a Child with Pilocytic Astrocytoma: A Case Report.

Proton beam therapy (PBT) is an effective pediatric brain tumor treatment. However, the resulting microstructural changes within and around irradiated tumors are unknown. We retrospectively applied diffusion tensor imaging (DTI) and free-water imaging (FWI) on diffusion-weighted magnetic resonance imaging (dMRI) data to monitor microstructural changes during the PBT and after 8 months in a pilocytic astrocytoma (PA) and normal-appearing white matter (NAWM). We evaluated the conventional MRI- and dMRI-derived indices from six MRI sessions (t0-t5) in a Caucasian child with a hypothalamic PA: at baseline (t0), during the PBT (t1-t4) and after 8 months (t5). The tumor voxels were classified as "solid" or "fluid" based on the FWI. While the tumor volume remained stable during the PBT, the dMRI analyses identified two different response patterns: (i) an increase in fluid content and diffusivity with anisotropy reductions in the solid voxels at t1, followed by (ii) smaller variations in fluid content but higher anisotropy in the solid voxels at t2-t4. At follow-up (t5), the tumor volume, fluid content, and diffusivity in the solid voxels increased. The NAWM showed dose-dependent microstructural changes. The use of the dMRI and FWI showed complex dynamic microstructural changes in the irradiated mass during the PBT and at follow-up, opening new avenues in our understanding of radiation-induced pathophysiologic mechanisms in tumors and the surrounding tissues.

Accurate proton treatment planning for pencil beam crossing titanium fixation implants.

PURPOSE: To present a planning strategy for proton pencil-beam scanning when titanium implants need to be crossed by the beam. METHODS: We addressed three issues: the implementation of a CT calibration curve to assign to titanium the correct stopping power; the effect of artefacts on CT images and their reduction by a dedicated algorithm; the differences in dose computation depending on the dose engine, pencil-beam vs Monte-Carlo algorithms. We performed measurement tests on a simple cylinder phantom and on a real implant. These phantoms were irradiated with three geometries (single spots, uniform mono-energetic layer and uniform box), measuring the exit dose either by radio-chromic film or multi-layer ionization chamber. The procedure was then applied on two patients treated for chordoma. RESULTS: We had to set in the calibration curve a mass density equal to 4.37 g/cm3 to saturated Hounsfield Units, in order to have the correct stopping power assigned to titanium in TPS. CT artefact reduction algorithm allowed a better reconstruction of the shape and size of the implant. Monte-Carlo resulted accurate in computing the dose distribution whereas the pencil-beam algorithm failed due to sharp density interfaces between titanium and the surrounding material. Finally, the treatment plans obtained on two patients showed the impact of the dose engine algorithm, with 10-20% differences between pencil-beam and Monte-Carlo in small regions distally to the titanium screws. CONCLUSION: The described combination of CT calibration, artefacts reduction and Monte-Carlo computation provides a reliable methodology to compute dose in patients with titanium implants.

Clinical implementation in proton therapy of multi-field optimization by a hybrid method combining conventional PTV with robust optimization.

To implement a robust multi-field optimization (MFO) technique compatible with the application of a Monte Carlo (MC) algorithm and to evaluate its robustness. Nine patients (three brain, five head-and-neck, one spine) underwent proton treatment generated by a novel robust MFO technique. A hybrid (hMFO) approach was implemented, planning dose coverage on isotropic PTV compensating for setup errors, whereas range calibration uncertainties are incorporated into PTV robust optimization process. hMFO was compared with single-field optimization (SFO) and full robust multi-field optimization (fMFO), both on the nominal plan and the worst-case scenarios assessed by robustness analysis. The SFO and the fMFO plans were normalized to hMFO on CTV to obtain iso-D95 coverage, and then the organs at risk (OARs) doses were compared. On the same OARs, in the normalized nominal plans the potential impact of variable relative biological effectiveness (RBE) was investigated. hMFO reduces the number of scenarios computed for robust optimization (from twenty-one in fMFO to three), making it practicable with the application of a MC algorithm. After normalizing on D95 CTV coverage, nominal hMFO plans were superior compared to SFO in terms of OARs sparing (p  < 0.01), without significant differences compared to fMFO. The improvement in OAR sparing with hMFO with respect to SFO was preserved in worst-case scenarios (p  < 0.01), confirming that hMFO is as robust as SFO to physical uncertainties, with no significant differences when compared to the worst case scenarios obtained by fMFO. The dose increase on OARs due to variable RBE was comparable to the increase due to physical uncertainties (i.e. 4-5 Gy(RBE)), but without significant differences between these techniques. hMFO allows improving plan quality with respect to SFO, with no significant differences with fMFO and without affecting robustness to setup, range and RBE uncertainties, making clinically feasible the application of MC-based robust optimization.

A new facility for proton radiobiology at the Trento proton therapy centre: Design and implementation.

We present a new facility dedicated to radiobiology research, which has been implemented at the Trento Proton Therapy Centre (Italy). A dual-ring double scattering system was designed to produce irradiation fields of two sizes (i.e. 6 and 16 cm diameter) starting from a fix pencil beam at 148 MeV. The modulation in depth was obtained with a custom-made range modulator, optimized to generate a 2.5 cm spread-out Bragg peak (SOBP). The resulting irradiation field was characterized in terms of lateral and depth-dose profiles. The beam characteristics and the geometry of the setup were implemented in the Geant4 Monte Carlo (MC) code. After benchmark against experimental data, the MC was used to characterize the distribution of dose-average linear energy transfer (LET) associated to the irradiation field. The results indicate that dose uniformity above 92.9% is obtained at the entrance channel as well as in the middle SOBP in the target regions for both irradiation fields. Dose rate in the range from 0.38 to 0.78 Gy/min was measured, which can be adjusted by proper selection of cyclotron output current, and eventually increased by about a factor 7. MC simulations were able to reproduce experimental data with good agreement. The characteristics of the facility are in line with the requirements of most radiobiology experiments. Importantly, the facility is also open to external users, after successful evaluation of beam proposals by the Program Advisory Committee.

A pre-absorber optimization technique for pencil beam scanning proton therapy treatments.

PURPOSE: To implement a new proton therapy planning method for the treatment of shallow lesions with PBS and to compare it to the standard method. METHODS AND MATERIALS: In order to treat shallow lesions, a pre-absorber, usually called range-shifter (RS), is needed: it is used to degrade the beam energy and treat tumors shallower than the minimum range available. Its use is associated to dose calculation uncertainties and plan quality degradation which should be minimized. We studied five tumor localizations requiring RS and created three plans for each case: a) standard method with the RS close to the patient surface, b) with the RS used only for the shallow part of the tumor (when strictly needed) and completely retracted and c) as the b) approach but with the RS close to the patient. We called these two approaches 'Range Shifter Optimization' (RSO) techniques. We compared those plans in terms of dose distribution quality, delivery time and patient-specific-QA results. RESULTS: In most cases a good dose reduction to OARs with no significant loss in terms of target coverage was obtained when the RSO techniques were used. Patient-specific-QA gave very good results in terms of γ-Passing-Rate (PR) (3%, 3 mm) for both RSO techniques (mean 98.09%), while the standard had some very low PR (minimum 81.09%). The delivery time increased (5.0 min on average per treatment) but was still acceptable in terms of patient compliance. CONCLUSION: We developed a new planning technique for shallow lesions and we demonstrated its superiority in terms of both plan quality and patient-specific-QA results with respect to the standard method. This technique is routinely used to treat patients in our center.

Implementation of proton therapy treatments with pencil beam scanning of targets with limited intrafraction motion.

PURPOSE: To report on the implementation, validation and results of the first two proton therapy PBS treatments of limited amplitudes moving targets performed at our center. METHODS AND MATERIALS: A real time optical tracking system was used to monitor the patient surface during the CT scan and treatment. This system is also able to trigger the beam during the treatment. A 4DCT (10 phases) and a Free-Breathing CT (FBCT) were used for the planning. The physician used the 4DCT for ITV delineation, while planning was performed on the FBCT. The approved plan was evaluated in two ways:The largest breathing amplitude recorded during 4DCT scan was used as gating safety threshold during treatment delivery. This planning and treatment workflow was then applied for two patients affected by thoracic thymoma. RESULTS: The dosimetric evaluation of the plan showed no interplay effect. The second patient showed an overdosage to the coronary and Left Anterior Descending area in the worst case scenario but it was below the constraints. Duty Cycle together with number of beam interruptions gave information about the patient compliance to the treatment: the first patient breath is stable and within thresholds, whilst the second patient had more variations, causing multiple beam interruptions. CONCLUSION: We defined and used for two patients a protocol for the treatment of small amplitude moving targets. The planning and delivery of the treatments gave very good results in terms of coverage, OARs sparing, 4D dose evaluation of the plan and interplay effect assessment.

Radiation-Induced Moyamoya Syndrome After Proton Therapy in Child with Clival Chordoma: Natural History and Surgical Treatment.

BACKGROUND: Proton therapy has proven to be effective and safe in the treatment of radioresistant skull base tumors such as chordomas. Thanks to the peculiar physical properties of the proton beam, radiation energy is delivered in a narrow space called the Bragg peak and the surrounding normal tissues receive a minimal amount of the radiation dose. This is important to lower the risk of radiation-induced damage, especially in children. However, local adverse effects in proximity to the target volume may occur. In particular, the development of moyamoya syndrome (MMS) has been rarely reported in children receiving proton beam therapy for brain tumors. CASE DESCRIPTION: We report on a child who developed rapidly progressive MMS after proton beam therapy for a clivus chordoma. A combined indirect revascularization procedure by encephalo-duro-arterio-synangiosis and encephalo-myo-synangiosis was performed with good neuroradiologic and clinical outcome. CONCLUSIONS: Regardless of the presence of known risk factors for MMS, strict neuroimaging surveillance is indicated in all patients treated with radiotherapy including those receiving proton beam therapy. We suggest that an early revascularization procedure should be considered in patients with worsening symptoms and/or sign of neuroradiologic progression of cerebral vasculopathy. This management of MMS could lower the risk of permanent neurologic deficits and improve patients' quality of life.

Impact of dose engine algorithm in pencil beam scanning proton therapy for breast cancer.

PURPOSE: Proton therapy for the treatment of breast cancer is acquiring increasing interest, due to the potential reduction of radiation-induced side effects such as cardiac and pulmonary toxicity. While several in silico studies demonstrated the gain in plan quality offered by pencil beam scanning (PBS) compared to passive scattering techniques, the related dosimetric uncertainties have been poorly investigated so far. METHODS: Five breast cancer patients were planned with Raystation 6 analytical pencil beam (APB) and Monte Carlo (MC) dose calculation algorithms. Plans were optimized with APB and then MC was used to recalculate dose distribution. Movable snout and beam splitting techniques (i.e. using two sub-fields for the same beam entrance, one with and the other without the use of a range shifter) were considered. PTV dose statistics were recorded. The same planning configurations were adopted for the experimental benchmark. Dose distributions were measured with a 2D array of ionization chambers and compared to APB and MC calculated ones by means of a γ analysis (agreement criteria 3%, 3 mm). RESULTS: Our results indicate that, when using proton PBS for breast cancer treatment, the Raystation 6 APB algorithm does not allow obtaining sufficient accuracy, especially with large air gaps. On the contrary, the MC algorithm resulted into much higher accuracy in all beam configurations tested and has to be recommended. CONCLUSIONS: Centers where a MC algorithm is not yet available should consider a careful use of APB, possibly combined with a movable snout system or in any case with strategies aimed at minimizing air gaps.

Improvements in pencil beam scanning proton therapy dose calculation accuracy in brain tumor cases with a commercial Monte Carlo algorithm.

A commercial Monte Carlo (MC) algorithm (RayStation version 6.0.024) for the treatment of brain tumors with pencil beam scanning (PBS) proton therapy is validated and compared via measurements and analytical calculations in clinically realistic scenarios. For the measurements a 2D ion chamber array detector (MatriXX PT) was placed underneath the following targets: (1) an anthropomorphic head phantom (with two different thicknesses) and (2) a biological sample (i.e. half a lamb's head). In addition, we compared the MC dose engine versus the RayStation pencil beam (PB) algorithm clinically implemented so far, in critical conditions such as superficial targets (i.e. in need of a range shifter (RS)), different air gaps, and gantry angles to simulate both orthogonal and tangential beam arrangements. For every plan the PB and MC dose calculations were compared to measurements using a gamma analysis metrics (3%, 3 mm). For the head phantom the gamma passing rate (GPR) was always >96% and on average >99% for the MC algorithm; the PB algorithm had a GPR of ⩽90% for all the delivery configurations with a single slab (apart 95% GPR from the gantry of 0° and small air gap) and in the case of two slabs of the head phantom the GPR was >95% only in the case of small air gaps for all three (0°, 45°, and 70°) simulated beam gantry angles. Overall the PB algorithm tends to overestimate the dose to the target (up to 25%) and underestimate the dose to the organ at risk (up to 30%). We found similar results (but a bit worse for the PB algorithm) for the two targets of the lamb's head where only two beam gantry angles were simulated. Our results suggest that in PBS proton therapy a range shifter (RS) needs to be used with caution when planning a treatment with an analytical algorithm due to potentially great discrepancies between the planned dose and the dose delivered to the patient, including in the case of brain tumors where this issue could be underestimated. Our results also suggest that a MC evaluation of the dose has to be performed every time the RS is used and, mostly, when it is used with large air gaps and beam directions tangential to the patient surface.

Supine craniospinal irradiation in pediatric patients by proton pencil beam scanning.

BACKGROUND AND PURPOSE: Proton therapy is the emerging treatment modality for craniospinal irradiation (CSI) in pediatric patients. Herein, special methods adopted for CSI at proton Therapy Center of Trento by pencil beam scanning (PBS) are comprehensively described. MATERIALS AND METHODS: Twelve pediatric patients were treated by proton PBS using two/three isocenters. Special methods refer to: (i) patient positioning in supine position on immobilization devices crossed by the beams; (ii) planning field-junctions via the ancillary-beam technique; (iii) achieving lens-sparing by three-beams whole-brain-irradiation; (iv) applying a movable-snout and beam-splitting technique to reduce the lateral penumbra. Patient-specific quality assurance (QA) program was performed using two-dimensional ion chamber array and γ-analysis. Daily kilovoltage alignment was performed. RESULTS: PBS allowed to obtain optimal target coverage (mean D98%>98%) with reduced dose to organs-at-risk. Lens sparing was obtained (mean D1∼730cGyE). Reducing lateral penumbra decreased the dose to the kidneys (mean Dmean<600cGyE). After kilovoltage alignment, potential dose deviations in the upper and lower junctions were small (average 0.8% and 1.2% respectively). Due to imperfect modeling of range shifter, QA showed better agreements between measurements and calculations at depths >4cm (mean γ>95%) than at depths<4cm. CONCLUSIONS: The reported methods allowed to effectively perform proton PBS CSI.

Reply to comment on 'Proton beam monitor chamber calibration'.

This reply shows that the discrepancy of about 3% between Faraday cup dosimetry and reference dosimetry using a cylindrical ionization chamber found in Gomà (2014 Phys. Med. Biol. 59 4961-71) seems to be due to an overestimation of the beam quality correction factors tabulated in IAEA TRS-398 for the cylindrical chamber used, rather than to 'unresolved problems with Faraday cup dosimetry', as suggested by Palmans and Vatnitsky (2016 Phys. Med. Biol. 61 6585-93). Furthermore, this work shows that a good agreement between reference dosimetry and Faraday cup dosimetry is possible, provided accurate beam quality correction factors for proton beams are used. The review on W air values presented by Palmans and Vatnitsky is believed to be inaccurate, as it is based on the imprecise assumption of ionization chamber perturbation correction factors in proton beams being equal to unity.

Is there a role for proton therapy in the treatment of hepatocellular carcinoma? A systematic review.

This paper aimed to review the literature concerning the use of proton therapy systematically in the treatment of hepatocellular carcinoma, focusing on clinical results and technical issues. The literature search was conducted according to a specific protocol in the Medline and Scopus databases by two independent researchers covering the period of 1990-2012. Both clinical and technical studies referring to a population of patients actually treated with protons were included. The PRISMA guidelines for reporting systematic reviews were followed. A final set of 16 studies from seven proton therapy institutions worldwide were selected from an initial dataset of 324 reports. Seven clinical studies, five reports on technical issues, three studies on treatment related toxicity and one paper reporting both clinical results and toxicity analysis were retrieved. Four studies were not published as full papers. Passive scattering was the most adopted delivery technique. More than 900 patients with heterogeneous stages of disease were treated with various fractionation schedules. Only one prospective full paper was found. Local control was approximately 80% at 3-5years, average overall survival at 5years was 32%, with data comparable to surgery in the most favorable groups. Toxicity was low (mainly gastrointestinal). Normal liver V0Gy<30%volume and V30Gy<18-25%volume were suggested as cut-off values for hepatic toxicity. The good clinical results of the selected papers are counterbalanced by a low level of evidence. However, the rationale to enroll patients in prospective studies appears to be strong.

Application of failure mode and effects analysis to treatment planning in scanned proton beam radiotherapy.

BACKGROUND: A multidisciplinary and multi-institutional working group applied the Failure Mode and Effects Analysis (FMEA) approach to the actively scanned proton beam radiotherapy process implemented at CNAO (Centro Nazionale di Adroterapia Oncologica), aiming at preventing accidental exposures to the patient. METHODS: FMEA was applied to the treatment planning stage and consisted of three steps: i) identification of the involved sub-processes; ii) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system, iii) 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: Thirty-four sub-processes were identified, twenty-two of them were judged to be potentially prone to one or more failure modes. A total of forty-four failure modes were recognized, 52% of them characterized by an RPN score equal to 80 or higher. The threshold of 125 for RPN was exceeded in five cases only. The most critical sub-process appeared related to the delineation and correction of artefacts in planning CT data. Failures associated to that sub-process were inaccurate delineation of the artefacts and incorrect proton stopping power assignment to body regions. Other significant failure modes consisted of an outdated representation of the patient anatomy, an improper selection of beam direction and of the physical beam model or dose calculation grid. The main effects of these failures were represented by wrong dose distribution (i.e. deviating from the planned one) delivered to the patient. Additional strategies for risk mitigation, easily and immediately applicable, consisted of a systematic information collection about any known implanted prosthesis directly from each patient and enforcing a short interval time between CT scan and treatment start. Moreover, (i) the investigation of dedicated CT image reconstruction algorithms, (ii) further evaluation of treatment plan robustness and (iii) implementation of independent methods for dose calculation (such as Monte Carlo simulations) may represent novel solutions to increase patient safety. CONCLUSIONS: FMEA is a useful tool for prospective evaluation of patient safety in proton beam radiotherapy. The application of this method to the treatment planning stage lead to identify strategies for risk mitigation in addition to the safety measures already adopted in clinical practice.