Publications by authors named "Alfredo Mirandola"

29 Publications

  • Page 1 of 1

How LEM-based RBE and dose-averaged LET affected clinical outcomes of sacral chordoma patients treated with carbon ion radiotherapy.

Radiother Oncol 2021 Sep 17;163:209-214. Epub 2021 Sep 17.

Fondazione CNAO, Pavia, Italy.

Purpose/objective: To understand the role of relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LET) distributions in the treatment of sacral chordoma (SC) patients with carbon ion radiotherapy (CIRT).

Material/methods: Clinical plans of 50 SC patients consecutively treated before August 2018 with a local effect model-based optimization were recalculated with the modified microdosimetric kinetic RBE model (mMKM). Twenty-six patients were classified as progressive disease and the relapse volume was contoured on the corresponding follow-up diagnostic sequence. The remaining 24 patients populated the control group. Target prescription dose (D), near-to-minimum- (D) and near-to-maximum- (D) doses were compared between the two cohorts in both RBE systems. LET distribution was evaluated for in-field relapsed cases with respect to the control group.

Results: Target D and D were respectively 10% and 18% lower than what we aimed at. Dosimetric evaluators showed no significant difference, in neither of the RBE frameworks, between relapsed and control sets. Half of the relapse volumes were located in a well-covered high dose region. On average, over these cases, median target LET was significantly lower than the control cohort mean value (27 vs 30 keV/μm). Most notably, the volume receiving dose from high-LET particles (>50 keV/μm) lay substantially below recently reported data in the literature.

Conclusion: A combined multi model RBE- and LET-based optimization could play a key role in the enhancement of the therapeutic ratio of CIRT for large radioresistant tumors such as sacral chordomas.
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http://dx.doi.org/10.1016/j.radonc.2021.08.024DOI Listing
September 2021

Particle Radiotherapy for Skull Base Chondrosarcoma: A Clinical Series from Italian National Center for Oncological Hadrontherapy.

Cancers (Basel) 2021 Sep 2;13(17). Epub 2021 Sep 2.

Clinical Department, National Center for Oncological Hadrontherapy (CNAO), 27100 Pavia, Italy.

Background: The standard treatment for skull base chondrosarcoma (SB-CHS) consists of surgery and high-dose radiation therapy. Our aim was to evaluate outcome in terms of local control (LC) and toxicity of proton therapy (PT) and carbon ion (CIRT) after surgery.

Materials And Methods: From September 2011 to July 2020, 48 patients underwent particle therapy (67% PT, 33% CIRT) for SB-CHS. PT and CIRT total dose was 70 GyRBE (relative biological effectiveness) in 35 fractions and 70.4 GyRBE in 16 fractions, respectively. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5).

Results: After a median follow-up time of 38 months, one local failure (2%) was documented and the patient died for progressive disease. Overall, 3-year LC was 98%. One (2%) and 4 (8%) patients experienced G3 acute and late toxicity, respectively. White-matter brain changes were documented in 22 (46%) patients, but only 7 needed steroids (G2). No patients had G3 brain toxicity. No G4-5 complications were reported. We did not find any correlation between high-grade toxicity or white-matter changes and characteristics of patients, disease and surgery.

Conclusions: PT and CIRT appeared to be effective and safe treatments for patients with SB-CHS, resulting in high LC rates and an acceptable toxicity profile.
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http://dx.doi.org/10.3390/cancers13174423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430859PMC
September 2021

A Multicentre Evaluation of Dosiomics Features Reproducibility, Stability and Sensitivity.

Cancers (Basel) 2021 Jul 30;13(15). Epub 2021 Jul 30.

Medical Physics Department, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy.

Dosiomics is a texture analysis method to produce dose features that encode the spatial 3D distribution of radiotherapy dose. Dosiomic studies, in a multicentre setting, require assessing the features' stability to dose calculation settings and the features' capability in distinguishing different dose distributions. Dose distributions were generated by eight Italian centres on a shared image dataset acquired on a dedicated phantom. Treatment planning protocols, in terms of planning target volume coverage and dose-volume constraints to the organs at risk, were shared among the centres to produce comparable dose distributions for measuring reproducibility/stability and sensitivity of dosiomic features. In addition, coefficient of variation (CV) was employed to evaluate the dosiomic features' variation. We extracted 38,160 features from 30 different dose distributions from six regions of interest, grouped by four features' families. A selected group of features (CV < 3 for the reproducibility/stability studies, CV > 1 for the sensitivity studies) were identified to support future multicentre studies, assuring both stable features when dose distributions variation is minimal and sensitive features when dose distribution variations need to be clearly identified. Dosiomic is a promising tool that could support multicentre studies, especially for predictive models, and encode the spatial and statistical characteristics of the 3D dose distribution.
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http://dx.doi.org/10.3390/cancers13153835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345157PMC
July 2021

Current Situation of Proton Therapy for Hodgkin Lymphoma: From Expectations to Evidence.

Cancers (Basel) 2021 Jul 26;13(15). Epub 2021 Jul 26.

Radiation Oncology Clinical Department, National Center for Oncological Hadrontherapy (CNAO), 27100 Pavia, Italy.

Consolidative radiation therapy (RT) is of prime importance for early-stage Hodgkin lymphoma (HL) management since it significantly increases progression-free survival (PFS). Nevertheless, first-generation techniques, relying on large irradiation fields, delivered significant radiation doses to critical organs-at-risk (OARs, such as the heart, to the lung or the breasts) when treating mediastinal HL; consequently, secondary cancers, and cardiac and lung toxicity were substantially increased. Fortunately, HL RT has drastically evolved and, nowadays, state-of-the-art RT techniques efficiently spare critical organs-at-risks without altering local control or overall survival. Recently, proton therapy has been evaluated for mediastinal HL treatment, due to its possibility to significantly reduce integral dose to OARs, which is expected to limit second neoplasm risk and reduce late toxicity. Nevertheless, clinical experience for this recent technique is still limited worldwide. Based on current literature, this critical review aims to examine the current practice of proton therapy for mediastinal HL irradiation.
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http://dx.doi.org/10.3390/cancers13153746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345146PMC
July 2021

Development and Implementation of Proton Therapy for Hodgkin Lymphoma: Challenges and Perspectives.

Cancers (Basel) 2021 Jul 26;13(15). Epub 2021 Jul 26.

Radiation Oncology Clinical Department, National Center for Oncological Hadrontherapy (CNAO), 27100 Pavia, Italy.

Consolidative radiation therapy for early-stage Hodgkin lymphoma (HL) improves progression-free survival. Unfortunately, first-generation techniques, relying on large irradiation fields, were associated with an increased risk of secondary cancers, and of cardiac and lung toxicity. Fortunately, the use of smaller target volumes combined with technological advances in treatment techniques currently allows efficient organs-at-risk sparing without altering tumoral control. Recently, proton therapy has been evaluated for mediastinal HL treatment due to its potential to significantly reduce the dose to organs-at-risk, such as cardiac substructures. This is expected to limit late radiation-induced toxicity and possibly, second-neoplasm risk, compared with last-generation intensity-modulated radiation therapy. However, the democratization of this new technique faces multiple issues. Determination of which patient may benefit the most from proton therapy is subject to intense debate. The development of new effective systemic chemotherapy and organizational, societal, and political considerations might represent impediments to the larger-scale implementation of HL proton therapy. Based on the current literature, this critical review aims to discuss current challenges and controversies that may impede the larger-scale implementation of mediastinal HL proton therapy.
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http://dx.doi.org/10.3390/cancers13153744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345082PMC
July 2021

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

Front Oncol 2021 10;11:601784. Epub 2021 Jun 10.

Dipartimento di Scienze di Base e Applicate per l'Ingegneria, Sapienza Università di Roma, Rome, Italy.

Particle therapy in which deep seated tumours are treated using C 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 C 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 C 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.
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http://dx.doi.org/10.3389/fonc.2021.601784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222779PMC
June 2021

High-dose hypofractionated pencil beam scanning carbon ion radiotherapy for lung tumors: Dosimetric impact of different spot sizes and robustness to interfractional uncertainties.

Phys Med 2021 May 10;85:79-86. Epub 2021 May 10.

CNAO, National Center for Oncological Hadrontherapy, Strada Campeggi 53, I-27100 Pavia, Italy.

Purpose: The robustness against setup and motion uncertainties of gated four-dimensional restricted robust optimization (4DRRO) was investigated for hypofractionated carbon ion radiotherapy (CIRT) of lung tumors.

Methods: CIRT plans of 9 patients were optimized using 4DRRO strategy with 3 mm setup errors, 3% density errors and 3 breathing phases related to the gate window. The prescription was 60 Gy(RBE) in 4 fractions. Standard spots (SS) were compared to big spots (BS). Plans were recalculated on multiple 4DCTs acquired within 3 weeks from treatment simulation and rigidly registered with planning images using bone matching. Warped dose distributions were generated using deformable image registration and accumulated on the planning 4DCTs. Target coverage (D98%, D95% and V95%) and dose to lung were evaluated in the recalculated and accumulated dose distributions.

Results: Comparable target coverage was obtained with both spot sizes (p = 0.53 for D95%). The mean lung dose increased of 0.6 Gy(RBE) with BS (p = 0.0078), still respecting the dose constraint of a 4-fraction stereotactic treatment for the risk of radiation pneumonitis. Statistically significant differences were found in the recalculated and accumulated D95% (p = 0.048 and p = 0.024), with BS showing to be more robust. Using BS, the average degradations of the D98%, D95% and V95% in the accumulated doses were -2.7%, -1.6% and -1.5%.

Conclusions: Gated 4DRRO was highly robust against setup and motion uncertainties. BS increased the dose to healthy tissues but were more robust than SS. The selected optimization settings guaranteed adequate target coverage during the simulated treatment course with acceptable risk of toxicity.
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http://dx.doi.org/10.1016/j.ejmp.2021.05.004DOI Listing
May 2021

Is a tailored strategy using proton beam radiotherapy for reirradiation advantageous for elderly women? A case report.

Tumori 2021 Apr 25:3008916211007930. Epub 2021 Apr 25.

Radiation Oncology, Clinical Department, National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy.

Background: The management of primary or recurrent vaginal tumours in an aging population is challenging for gynecologic and radiation oncologists. In patients unsuited for surgery and already irradiated on the pelvis, proton beam radiotherapy may be worthwhile due to its ballistic advantages.

Case Report: We report the case of an 80-year-old woman with a squamous cell carcinoma of the vagina after a history of pelvic radiation and vaginal brachytherapy delivered for a previous endometrial adenocarcinoma. She received proton beam radiotherapy with a complete response after 12 months and mild toxicity.

Conclusions: The complexity of reirradiation management in the frail and elderly population requires attention. Efforts should be focused on maintaining autonomy and quality of life in order to improve adherence and clinical compliance to the treatment. In the era of the tailored approach, hadrontherapy can play an important role to minimize toxicity, obtain good local control, and reduce the overall treatment time.
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http://dx.doi.org/10.1177/03008916211007930DOI Listing
April 2021

Endometrial Cancer: When Upfront Surgery Is Not an Option.

Oncology 2021 8;99(2):65-71. Epub 2020 Oct 8.

Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy.

Background and Summary: The management of endometrial cancer, in an ever-older population with considerable comorbidity, remains a challenge for gynecological and radiation oncologists. Key Message: The present paper reviews literature data on treatment options for endometrial cancer patients unfit for surgery.
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http://dx.doi.org/10.1159/000510690DOI Listing
February 2021

Re-irradiation With Carbon Ion Radiotherapy for Pelvic Rectal Cancer Recurrences in Patients Previously Irradiated to the Pelvis.

In Vivo 2020 May-Jun;34(3):1547-1553

National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy.

Background/aim: Re-irradiation of locally recurrent rectal cancer poses challenges due to the proximity of critical organs, such as the bowel. This study aimed at evaluating the safety and efficacy of re-irradiation with Carbon Ion Radiotherapy (CIRT) in rectal cancer patients with local recurrence.

Patients And Methods: Between 2014 and 2018, 14 patients were treated at the National Center of Oncological Hadrontherapy (CNAO Foundation) with CIRT for locally recurrent rectal cancer.

Results: All patients concluded the treatment. No G≥3 acute/late reaction nor pelvic infections were observed. The 1-year and 2-year local control rates were, 78% and 52%, respectively, and relapse occurred close to the bowel in 6 patients. The 1-year and 2-year overall survival rates were 100% and 76.2% each; while the 1-year and 2-year metastasis free survival rates were 64.3% and 43%.

Conclusion: CIRT as re-irradiation for locally recurrent rectal cancer emerges as a safe and valid treatment with an acceptable rate of morbidity of surrounding healthy tissue.
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http://dx.doi.org/10.21873/invivo.11944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279804PMC
February 2021

Proton and carbon ion radiotherapy in skull base chordomas: a prospective study based on a dual particle and a patient-customized treatment strategy.

Neuro Oncol 2020 09;22(9):1348-1358

Scientific Directorate, European Institute of Oncology, IRCCS, Milan, Italy.

Background: The aim of this study is to evaluate results in terms of local control (LC), overall survival (OS), and toxicity profile and to better identify factors influencing clinical outcome of skull base chordoma treated with proton therapy (PT) and carbon ion radiotherapy (CIRT).

Methods: We prospectively collected and analyzed data of 135 patients treated between November 2011 and December 2018. Total prescription dose in the PT group (70 patients) and CIRT group (65 patients) was 74 Gy relative biological effectiveness (RBE) delivered in 37 fractions and 70.4 Gy(RBE) delivered in 16 fractions, respectively (CIRT in unfavorable patients). LC and OS were evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were performed, to identify prognostic factors on clinical outcomes.

Results: After a median follow-up of 44 (range, 6-87) months, 14 (21%) and 8 (11%) local failures were observed in CIRT and PT group, respectively. Five-year LC rate was 71% in CIRT cohort and 84% in PT cohort. The estimated 5-year OS rate in the CIRT and PT group was 82% and 83%, respectively. On multivariate analysis, gross tumor volume (GTV), optic pathways, and/or brainstem compression and dose coverage are independent prognostic factors of local failure risk. High rate toxicity grade ≥3 was reported in 11% of patients.

Conclusions: Particle radiotherapy is an effective treatment for skull base chordoma with acceptable late toxicity. GTV, optic pathways, and/or brainstem compression and target coverage were independent prognostic factors for LC.

Key Points: • Proton and carbon ion therapy are effective and safe in skull base chordoma.• Prognostic factors are GTV, organs at risk compression, and dose coverage.• Dual particle therapy and customized strategy was adopted.
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http://dx.doi.org/10.1093/neuonc/noaa067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523440PMC
September 2020

Is Proton Beam Radiotherapy Worthwhile in the Management of Angiosarcoma of the Scalp?

Anticancer Res 2020 Mar;40(3):1645-1649

National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy.

In inoperable patients, the management of angiosarcoma of the scalp is challenging. Due to intrinsic, dosimetric and radiobiological properties, proton beam radiotherapy may be an effective and safe option to offer to these difficult-to-cure patients. Here, we report a case of angiosarcoma of the scalp treated successfully with proton beam radiotherapy. Angiosarcoma is a rare malignancy concerning around 2% of soft-tissue sarcomas and 5% of cutaneous soft-tissue sarcomas. Cutaneous angiosarcomas can occur in any part of the body, but the head and neck region is a common primary site and the scalp is a frequent site in elderly patients.
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http://dx.doi.org/10.21873/anticanres.14114DOI Listing
March 2020

Characterization of a MLIC Detector for QA in Scanned Proton and Carbon Ion Beams.

Int J Part Ther 2019 26;6(2):50-59. Epub 2019 Nov 26.

Fondazione CNAO (Italian National Center for Oncological Hadronterapy), Pavia, Italy.

Purpose: Beam energy validation is a fundamental aspect of the routine quality assurance (QA) protocol of a particle therapy facility. A multilayer ionization chamber (MLIC) detector provides the optimal tradeoff between achieving accuracy in particle range determination and saving operational time in measurements and analysis procedures. We propose the characterization of a commercial MLIC as a suitable QA tool for a clinical environment with proton and carbon-ion scanning beams.

Materials And Methods: Commercial MLIC Giraffe (IBA Dosimetry, Schwarzenbruck, Germany) was primarily evaluated in terms of short-term and long-term stability, linearity with dose, and dose-rate independence. Accuracy was tested by analyzing range of integrated depth-dose curves for a set of representative energies against reference acquisitions in water for proton and carbon ion beams; in addition, 2 modulated proton spread-out Bragg peaks were also measured. Possible methods to increase the native spatial resolution of the detector were also investigated.

Results: Measurements showed a high repeatability: mean relative standard deviation was within 0.5% for all channels and both particle types. The long-term stability of the gain calibration showed discrepancies less than 1% at different times. The detector response was linear with dose ( > 0.99) and independent on the dose rate. Measurements of integrated depth-dose curve ranges revealed a mean deviation from reference measurements in water of 0.1 ± 0.3 mm for protons with a maximum difference of 0.4 mm and 0.2 ± 0.6 mm with maximum difference of 0.85 mm for carbon ion beams. For the 2 modulated proton spread-out Bragg peaks, measured differences in distal dose falloff were ≤0.5 mm against calculated values.

Conclusions: The detector is stable, linearly responding with dose, precise, and easy to handle for QA beam energy checks of proton and carbon ion beams.
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http://dx.doi.org/10.14338/IJPT-19-00064.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986401PMC
November 2019

Rectum Dose Constraints for Carbon Ion Therapy: Relative Biological Effectiveness Model Dependence in Relation to Clinical Outcomes.

Cancers (Basel) 2019 Dec 21;12(1). Epub 2019 Dec 21.

Clinical Department, Centro Nazionale di Adroterapia Oncologica, 27100, Pavia, Italy.

The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma ( = 22) and sacral chordoma ( = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (D and D) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: DVHs lay largely below original constraints; the translated D values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal D of the rectum volume, v-1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are D ≤ 61 Gy(RBE) and D ≤ 66 Gy(RBE).
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http://dx.doi.org/10.3390/cancers12010046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016830PMC
December 2019

RBE-weighted dose in carbon ion therapy for ACC patients: Impact of the RBE model translation on treatment outcomes.

Radiother Oncol 2019 12 12;141:227-233. Epub 2019 Sep 12.

Clinical Department, National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy.

Purpose/objective: The purpose of this study is to assess the impact of the conversion scheme for relative biological effectiveness (RBE)-weighted dose (D), implemented at our center, on treatment outcomes of adenoid cystic carcinoma (ACC) patients.

Material/methods: Treatment plans of 78 ACC patients, optimized with the Local Effect Model (LEM), were recalculated with the modified Microdosimetric Kinetic Model (mMKM). D to 95%, 50% and 2% (D) of the clinical target volume (CTV), were selected as relevant parameters to compare LEM and mMKM D. The pattern of failure of ACC treatments was analyzed in relation to uncertainties involved in the D translation methodology.

Results: mMKM recalculations of LEM plans, optimized to a prescription dose of 68.8 Gy(RBE), showed a D 8% higher, on average, than the expected value (60.8 Gy(RBE)), closer to the most frequently used mMKM prescription D (64 Gy(RBE)). D and D deviations, with respect to the optimization goals in the two RBE systems, increased of 0.5% and 14.2%, respectively, due to the steeper mMKM RBE variation along the beam path. Local recurrences were mainly (63%) reported in areas where CTV coverage was not satisfactory in the original LEM plan and the mMKM analysis showed that OARs constraints were too conservative.

Conclusion: No case of local recurrence could be explained by inadequate mMKM target coverage that was not already present in the LEM plan. New constraints have been defined for optic pathways and brainstem to improve target coverage with no expected increase in tissue complications.
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http://dx.doi.org/10.1016/j.radonc.2019.08.022DOI Listing
December 2019

Impact of TPS calculation algorithms on dose delivered to the patient in proton therapy treatments.

Phys Med Biol 2019 04 4;64(7):075016. Epub 2019 Apr 4.

Fondazione CNAO, Strada Campeggi 53, 27100 Pavia, Italy. Author to whom any correspondence should be addressed.

To estimate the impact of dose calculation approaches adopted in different treatment planning systems (TPSs) on proton therapy dose delivered with pencil beam scanning (PBS). Treatment plans for six regular volumes in water and 15 clinical cases were optimized with Syngo-VC13 and exported for forward recalculation with Raystation-V7.0 pencil beam (RS-PBA) and Monte Carlo (RS-MC) algorithms and with the independent Fluka-MC engine. To verify clinical consistency between the two TPS dosimetric outcomes, the average percentage variations of clinical target volume (CTV) D , D and D , adopted for plan prescription and evaluation, were considered. Ionization chamber measurements served as a further reference for comparison in homogeneous conditions. CTV dose volume histogram (DVH) analysis and gamma evaluation with 3 mm-3% agreement criteria quantified the dose deviation of TPS calculation algorithms, in heterogeneous conditions, against the Fluka-MC code. CTV D , representing the plan dose prescription goal, was higher on average over H&N cases of (3.9  ±  0.9)% and (2.3  ±  0.6)% as calculated with RS-PBA and RS-MC, respectively, compared to Syngo. For tumors located in the pelvis district, average D variations of (1.6  ±  0.7)% and (1.2  ±  0.7)% were found. Syngo underestimated target near maximum doses with respect to all computation systems. Calculation accuracy in heterogeneous conditions of RS-PBA H&N plans resulted poor when a range shifter was required. Target DVH and γ-analysis showed excellent agreement between RS-MC and Fluka-MC, with γ-pass rates  >98% for all patient groups. Different TPS dose calculation approaches mainly affected dose delivered in H&N proton treatments, while minor deviations were found for pelvic tumors. RS-MC proved to be the most accurate TPS dose calculation algorithm when compared to an independent MC simulation code.
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http://dx.doi.org/10.1088/1361-6560/ab0a4dDOI Listing
April 2019

Design and commissioning of the non-dedicated scanning proton beamline for ocular treatment at the synchrotron-based CNAO facility.

Med Phys 2019 Apr 14;46(4):1852-1862. Epub 2019 Feb 14.

Fondazione CNAO, strada Campeggi 53, 27100, Pavia, Italy.

Purpose: Only few centers worldwide treat intraocular tumors with proton therapy, all of them with a dedicated beamline, except in one case in the USA. The Italian National Center for Oncological Hadrontherapy (CNAO) is a synchrotron-based hadrontherapy facility equipped with fixed beamlines and pencil beam scanning modality. Recently, a general-purpose horizontal proton beamline was adapted to treat also ocular diseases. In this work, the conceptual design and main dosimetric properties of this new proton eyeline are presented.

Methods: A 28 mm thick water-equivalent range shifter (RS) was placed along the proton beamline to shift the minimum beam penetration at shallower depths. FLUKA Monte Carlo (MC) simulations were performed to optimize the position of the RS and patient-specific collimator, in order to achieve sharp lateral dose gradients. Lateral dose profiles were then measured with radiochromic EBT3 films to evaluate the dose uniformity and lateral penumbra width at several depths. Different beam scanning patterns were tested. Discrete energy levels with 1 mm water-equivalent step within the whole ocular energy range (62.7-89.8 MeV) were used, while fine adjustment of beam range was achieved using thin polymethylmethacrylate additional sheets. Depth-dose distributions (DDDs) were measured with the Peakfinder system. Monoenergetic beam weights to achieve flat spread-out Bragg Peaks (SOBPs) were numerically determined. Absorbed dose to water under reference conditions was measured with an Advanced Markus chamber, following International Atomic Energy Agency (IAEA) Technical Report Series (TRS)-398 Code of Practice. Neutron dose at the contralateral eye was evaluated with passive bubble dosimeters.

Results: Monte Carlo simulations and experimental results confirmed that maximizing the air gap between RS and aperture reduces the lateral dose penumbra width of the collimated beam and increases the field transversal dose homogeneity. Therefore, RS and brass collimator were placed at about 98 cm (upstream of the beam monitors) and 7 cm from the isocenter, respectively. The lateral 80%-20% penumbra at middle-SOBP ranged between 1.4 and 1.7 mm depending on field size, while 90%-10% distal fall-off of the DDDs ranged between 1.0 and 1.5 mm, as a function of range. Such values are comparable to those reported for most existing eye-dedicated facilities. Measured SOBP doses were in very good agreement with MC simulations. Mean neutron dose at the contralateral eye was 68 μSv/Gy. Beam delivery time, for 60 Gy relative biological effectiveness (RBE) prescription dose in four fractions, was around 3 min per session.

Conclusions: Our adapted scanning proton beamline satisfied the requirements for intraocular tumor treatment. The first ocular treatment was delivered in August 2016 and more than 100 patients successfully completed their treatment in these 2 yr.
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http://dx.doi.org/10.1002/mp.13389DOI Listing
April 2019

Characterization of a multilayer ionization chamber prototype for fast verification of relative depth ionization curves and spread-out-Bragg-peaks in light ion beam therapy.

Med Phys 2018 May 6;45(5):2266-2277. Epub 2018 Apr 6.

Centro Nazionale di Adroterapia Oncologica (CNAO Foundation), Pavia, 27100, Italy.

Purpose: To dosimetrically characterize a multilayer ionization chamber (MLIC) prototype for quality assurance (QA) of pristine integral ionization curves (ICs) and spread-out-Bragg-peaks (SOBPs) for scanning light ion beams.

Methods: QUBE (De.Tec.Tor., Torino, Italy) is a modular detector designed for QA in particle therapy (PT). Its main module is a MLIC detector, able to evaluate particle beam relative depth ionization distributions at different beam energies and modulations. The charge collecting electrodes are made of aluminum, for a nominal water equivalent thickness (WET) of ~75 mm. The detector prototype was calibrated by acquiring the signals in the initial plateau region of a pristine BP and in terms of WET. Successively, it was characterized in terms of repeatability response, linearity, short-term stability and dose rate dependence. Beam-induced measurements of activation in terms of ambient dose equivalent rate were also performed. To increase the detector coarse native spatial resolution (~2.3 mm), several consecutive acquisitions with a set of certified 0.175-mm-thick PMMA sheets (Goodfellow, Cambridge Limited, UK), placed in front of the QUBE mylar entrance window, were performed. The ICs/SOBPs were achieved as the result of the sum of the set of measurements, made up of a one-by-one PMMA layer acquisition. The newly obtained detector spatial resolution allowed the experimental measurements to be properly comparable against the reference curves acquired in water with the PTW Peakfinder. Furthermore, QUBE detector was modeled in the FLUKA Monte Carlo (MC) code following the technical design details and ICs/SOBPs were calculated.

Results: Measurements showed a high repeatability: mean relative standard deviation within ±0.5% for all channels and both particle types. Moreover, the detector response was linear with dose (R  > 0.998) and independent on the dose rate. The mean deviation over the channel-by-channel readout respect to the reference beam flux (100%) was equal to 0.7% (1.9%) for the 50% (20%) beam flux level. The short-term stability of the gain calibration was very satisfying for both particle types: the channel mean relative standard deviation was within ±1% for all the acquisitions performed at different times. The ICs obtained with the MLIC QUBE at improved resolution satisfactorily matched both the MC simulations and the reference curves acquired with Peakfinder. Deviations from the reference values in terms of BP position, peak width and distal fall-off were submillimetric for both particle types in the whole investigated energy range. For modulated SOBPs, a submillimetric deviation was found when comparing both experimental MLIC QUBE data against the reference values and MC calculations. The relative dose deviations for the experimental MLIC QUBE acquisitions, with respect to Peakfinder data, ranged from ~1% to ~3.5%. Maximum value of 14.1 μSv/h was measured in contact with QUBE entrance window soon after a long irradiation with carbon ions.

Conclusion: MLIC QUBE appears to be a promising detector for accurately measuring pristine ICs and SOBPs. A simple procedure to improve the intrinsic spatial resolution of the detector is proposed. Being the detector very accurate, precise, fast responding, and easy to handle, it is therefore well suited for daily checks in PT.
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http://dx.doi.org/10.1002/mp.12866DOI Listing
May 2018

Abstract ID: 241 Geant4 simulation studies of secondary particles emission in hadrontherapy treatments.

Phys Med 2018 Jan;45 Suppl 1:S4-S5

University of Pavia, via Bassi 6, 27100 Pavia, Italy.

The aim of this work is the full simulation with Geant4 (vs. 10.0.p03) of secondary particles emitted during an hadrontherapy treatment with C. An accurate study of the ion beam fragmentation is important for both the evaluation of secondaries field inside and outside the target volume (i.e. for radioprotection and biological effects evaluation) and the prediction of nuclear particle interactions and their reaction products. In this study we investigate the depth energy deposition (Bragg curve) and the rate of secondary particles produced in the interaction between C and targets of different materials (water and Plexiglas). Simple irradiation setup was first implemented for a preliminary comparison of the Geant4 code with literature studies [1,2]. A good agreement (∼0.04%) was found for the Bragg peak position and the peak-to-plateau ratio (∼0.3%). The complete CNAO [3] (Centro Nazionale di Adroterapia Oncologica) extraction beamline with the target water phantom was then simulated for a characterization of secondary particles energy deposition along the beam axis, angular distributions for outgoing protons, neutrons, heavy secondary particles and prompt gammas. An agreement within 0.03% was found for the Bragg peak position with respect to CNAO data and Fluka simulation for 279.97 MeV/u C, highlighting the reliability of the Geant4 simulation. Preliminary results agree with literature studies but experimental data are needed to validate the code. Comparisons with additional simulation codes are foreseen. Geant4 simulations studies to predict the development of different physical processes as a function of the beam energy are also ongoing for both protons and carbon ions.
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http://dx.doi.org/10.1016/j.ejmp.2017.11.033DOI Listing
January 2018

Risk of carotid blowout after reirradiation with particle therapy.

Adv Radiat Oncol 2017 Jul-Sep;2(3):465-474. Epub 2017 Jul 6.

National Centre of Hadrontherapy (CNAO), Pavia, Italy.

Purpose: Carotid blowout (CB) is a serious complication in retreatment of neoplasms in the head and neck (H&N) region. Rates seem to increase in hypofractionated or accelerated hyperfractionated regimens. In this study, we investigate the CB rate and the cumulative doses received by the carotid artery (CA) in a cohort of patients who were reirradiated at CNAO with particle therapy in the H&N region.

Methods And Materials: The dosimetric information, medical records, and tumor characteristics of 96 patients were analyzed. For 49 of these patients, the quality of dosimetric information was sufficient to calculate the cumulative doses to the CA. The corresponding biological equivalent dose in 2 Gy fractions (EQD2) was calculated with an α/β-ratio of 3.

Results: In the final reirradiation at CNAO, 17 patients (18%) had been treated with protons and 79 (82%) with carbon ions. Two patients experienced profuse oronasal bleeding, of which one case was confirmed to be caused by CB. If attributing both cases to CB, we found an actuarial CB rate of 2.7%. Interestingly, there were no CB cases in the carbon ion group even though this was the large majority of patients and they generally were treated more aggressively in terms of larger fraction doses and higher cumulative EQD2.

Conclusions: The current practice of particle reirradiation at CNAO for recurrent neoplasms in the H&N region results in acceptable rates of CB.
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http://dx.doi.org/10.1016/j.adro.2017.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605322PMC
July 2017

Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams.

Phys Med Biol 2017 01 20;62(2):377-393. Epub 2016 Dec 20.

Dipartimento di Fisica 'Ettore Pancini', Università di Napoli Federico II, and INFN Sezione di Napoli, Napoli, Italy.

We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth-dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry.
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http://dx.doi.org/10.1088/1361-6560/aa5078DOI Listing
January 2017

Commissioning of the 4-D treatment delivery system for organ motion management in synchrotron-based scanning ion beams.

Phys Med 2016 Dec 24;32(12):1667-1671. Epub 2016 Nov 24.

Fondazione CNAO, Strada Campeggi 53, 27100 Pavia, Italy; Dipartimento di Elettronica Informazione e Bioingegneria, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy.

Purpose: The aim of this work was the commissioning of delivery procedures for the treatment of moving targets in scanning pencil beam hadrontherapy.

Methods: EBT3 films fixed to the Anzai Respiratory Phantom were exposed to carbon ion scanned homogeneous fields (E=332MeV/u). To evaluate the interplay effect, field size and flatness for 3 different scenarios were compared to static condition: gated irradiation or repainting alone and combination of both. Respiratory signal was provided by Anzai pressure sensor or optical tracking system (OTS). End-exhale phase and 1s gating window were chosen (2.5mm residual motion). Dose measurements were performed using a PinPoint ionization chamber inserted into the Brainlab ET Gating Phantom. A sub-set of tests was also performed using proton beams.

Results: The combination of gating technique and repainting (N=5) showed excellent results (6.1% vs 4.3% flatness, identical field size and dose deviation within 1.3%). Treatment delivery time was acceptable. Dose homogeneity for gated irradiation alone was poor. Both Anzai sensor and OTS appeared suitable for providing respiratory signal. Comparisons between protons and carbon ions showed that larger beam spot sizes represent more favorable condition for minimizing motion effect.

Conclusion: Results of measurements performed on different phantoms showed that the combination of gating and layered repainting is suitable to treat moving targets using scanning ion beams. Abdominal compression using thermoplastic masks, together with multi-field planning approach and multi-fractionation, have also been assessed as additional strategies to mitigate the effect of patient respiration in the clinical practice.
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http://dx.doi.org/10.1016/j.ejmp.2016.11.107DOI Listing
December 2016

Dose prescription in carbon ion radiotherapy: How to compare two different RBE-weighted dose calculation systems.

Radiother Oncol 2016 08 6;120(2):307-12. Epub 2016 Jul 6.

CNAO Foundation, Pavia, Italy; Istituto Europeo di Oncologia, Milano, Italy.

Background And Purpose: In carbon ion radiotherapy (CIRT), the use of different relative biological effectiveness (RBE) models in the RBE-weighted dose (DRBE) calculation can lead to deviations in the physical dose (Dphy) delivered to the patient. Our aim is to reduce target Dphy deviations by converting prescription dose values.

Material And Methods: Planning data of patients treated at the National Institute of Radiological Sciences (NIRS) were collected, with prescribed doses per fraction ranging from 3.6Gy (RBE) to 4.6Gy (RBE), according to the Japanese semi-empirical model. The Dphy was Monte Carlo (MC) re-calculated simulating the NIRS beamline. The local effect model (LEM)_I was then applied to estimate DRBE. Target median DRBE ratios between MC+LEM_I and NIRS plans determined correction factors for the conversion of prescription doses. Plans were re-optimized in a LEM_I-based commercial system, prescribing the NIRS uncorrected and corrected DRBE.

Results: The MC+LEM_I target median DRBE was respectively 15% and 5% higher than the NIRS reference, for the lowest and highest dose levels. Uncorrected DRBE prescription resulted in significantly lower target Dphy in re-optimized plans, with respect to NIRS plans.

Conclusions: Prescription dose conversion factors could minimize target physical dose variations due to the use of different radiobiological models in the calculation of CIRT RBE-weighted dose.
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http://dx.doi.org/10.1016/j.radonc.2016.05.031DOI Listing
August 2016

Dosimetric commissioning and quality assurance of scanned ion beams at the Italian National Center for Oncological Hadrontherapy.

Med Phys 2015 Sep;42(9):5287-300

Fondazione CNAO, strada Campeggi 53, Pavia 27100, Italy and Radiotherapy Division, European Institute of Oncology, Via Ripamonti 435, Milano 20141, Italy.

Purpose: To describe the dosimetric commissioning and quality assurance (QA) of the actively scanned proton and carbon ion beams at the Italian National Center for Oncological Hadrontherapy.

Methods: The laterally integrated depth-dose-distributions (IDDs) were acquired with the PTW Peakfinder, a variable depth water column, equipped with two Bragg peak ionization chambers. fluka Monte Carlo code was used to generate the energy libraries, the IDDs in water, and the fragment spectra for carbon beams. EBT3 films were used for spot size measurements, beam position over the scan field, and homogeneity in 2D-fields. Beam monitor calibration was performed in terms of number of particles per monitor unit using both a Farmer-type and an Advanced Markus ionization chamber. The beam position at the isocenter, beam monitor calibration curve, dose constancy in the center of the spread-out-Bragg-peak, dose homogeneity in 2D-fields, beam energy, spot size, and spot position over the scan field are all checked on a daily basis for both protons and carbon ions and on all beam lines.

Results: The simulated IDDs showed an excellent agreement with the measured experimental curves. The measured full width at half maximum (FWHM) of the pencil beam in air at the isocenter was energy-dependent for both particle species: in particular, for protons, the spot size ranged from 0.7 to 2.2 cm. For carbon ions, two sets of spot size are available: FWHM ranged from 0.4 to 0.8 cm (for the smaller spot size) and from 0.8 to 1.1 cm (for the larger one). The spot position was accurate to within ± 1 mm over the whole 20 × 20 cm(2) scan field; homogeneity in a uniform squared field was within ± 5% for both particle types at any energy. QA results exceeding tolerance levels were rarely found. In the reporting period, the machine downtime was around 6%, of which 4.5% was due to planned maintenance shutdowns.

Conclusions: After successful dosimetric beam commissioning, quality assurance measurements performed during a 24-month period show very stable beam characteristics, which are therefore suitable for performing safe and accurate patient treatments.
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http://dx.doi.org/10.1118/1.4928397DOI Listing
September 2015

Scan path optimization with/without clustering for active beam delivery in charged particle therapy.

Phys Med 2015 Mar 20;31(2):130-6. Epub 2015 Jan 20.

Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milan 20133, Italy; Bioengineering Unit, Centro Nazionale di Adroterapia Oncologica, Pavia 27100, Italy.

Purpose: To compare different algorithms to optimize the scanning path in charged particle therapy with quasidiscrete scanning. We implemented a Hybrid Genetic Algorithm with Heuristics (HyGA) and combined it with clustering techniques. The performance was compared to Simulated Annealing (SA) and to commercially available treatment planning system (TPS).

Methods: Performance and clinical implications were assessed using data from 10 patients treated at CNAO (Centro Nazionale di Adroterapia Oncologica). Clinical treatments are performed relying on beam deflection, avoiding irradiation for transitions between adjacent spots larger than 2 cm. A clustering method was implemented with HyGA (HyGA_Cl), which assumes beam deflection during transition between clusters. Clinical performance was determined as the total number of particles delivered during spot transitions and the number of particles wasted due to beam deflection. Results were compared to scan paths obtained with CNAO TPS.

Results: SA and HyGA produced on average shorter paths compared to the currently available TPS. This did not result in a reduction of transit particles, due to the concomitant effect of beam deflection out of the extraction line. HyGA_Cl achieved 2% average reduction in transit particles when compared to CNAO TPS. As a drawback, wasted particles increased, due to more frequent use of beam deflection. Both the SA and HyGA algorithms reduced the number of wasted particles.

Conclusion: SA and HyGA proved to be the most cost-effective methods in reducing wasted particles, with benefits in terms of shorter scan paths. A decrease in transit particles delivered with beam deflection can be achieved using HyGA_Cl.
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http://dx.doi.org/10.1016/j.ejmp.2015.01.001DOI Listing
March 2015

Proton beam radiotherapy: report of the first ten patients treated at the "Centro Nazionale di Adroterapia Oncologica (CNAO)" for skull base and spine tumours.

Radiol Med 2014 Apr 12;119(4):277-82. Epub 2013 Dec 12.

Fondazione CNAO, Strada Privata Campeggi, 27100, Pavia, Italy,

Purpose: The Italian National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO), equipped with a proton and ion synchrotron, started clinical activity in September 2011. The clinical and technical characteristics of the first ten proton beam radiotherapy treatments are reported.

Materials And Methods: Ten patients, six males and four females (age range 27-73 years, median 55.5), were treated with proton beam radiotherapy. After one to two surgical procedures, seven patients received a histological diagnosis of chordoma (of the skull base in three cases, the cervical spine in one case and the sacrum in three cases) and three of low-grade chondrosarcoma (skull base). Prescribed doses were 74 GyE for chordoma and 70 GyE for chondrosarcoma at 2 GyE/fraction delivered 5 days per week.

Results: Treatment was well tolerated without toxicity-related interruptions. The maximal acute toxicity was grade 2, with oropharyngeal mucositis, nausea and vomiting for the skull base tumours, and grade 2 dermatitis for the sacral tumours. After 6-12 months of follow-up, no patient developed tumour progression.

Conclusions: The analysis of the first ten patients treated with proton therapy at CNAO showed that this treatment was feasible and safe. Currently, patient accrual into these as well as other approved protocols is continuing, and a longer follow-up period is needed to assess tumour control and late toxicity.
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http://dx.doi.org/10.1007/s11547-013-0345-0DOI Listing
April 2014

Proton beam radiotherapy: report of the first patient treated at the Centro Nazionale di Adroterapia Oncologica (CNAO) [National Center of Oncologic Hadron Therapy].

Tumori 2013 Mar-Apr;99(2):e34-7

Fondazione CNAO, Pavia, Italy.

Proton beam radiotherapy, an innovative treatment modality, allows delivery of high radiation doses to the target while sparing surrounding healthy structures. The Centro Nazionale di Adroterapia Oncologica (CNAO), equipped with a synchrotron and capable of using both protons and ions, initiated its clinical activity in September 2011. The first treatment of a skull base tumor with protons is reported here. The case of a 26-year-old man with an intracranial low-grade chondrosarcoma of the right petroclival junction is discussed with emphasis on technical and clinical details. Two previous surgical interventions had achieved partial removal of the tumor and the patient was treated with protons for residual disease. The prescribed dose was 70 GyE in 35 fractions of 2 GyE. Treatment was completed with minimal acute toxicity consisting of grade 1 alopecia and nausea. Nine months after treatment the disease is locally controlled. Use of high-energy protons at CNAO is a safe and effective means of treating a tumor located near critical normal structures.
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http://dx.doi.org/10.1700/1283.14204DOI Listing
August 2013

Dose prescription in carbon ion radiotherapy: a planning study to compare NIRS and LEM approaches with a clinically-oriented strategy.

Phys Med Biol 2012 Nov 26;57(22):7543-54. Epub 2012 Oct 26.

Centro Nazionale di Adroterapia Oncologica, Pavia, Italy.

In carbon ion radiotherapy there is an urgent clinical need to develop objective tools for the conversion of relative biological effectiveness (RBE)-weighted doses based on different models. In this work we introduce a clinically oriented method to compare NIRS-based and LEM-based GyE systems, minimizing differences in physical dose distributions between treatment plans. Carbon ion plans were optimized on target volumes of cubic and spherical shapes, for RBE-weighted dose prescription levels ranging from 3.6 to 4.4 GyE. Plans were calculated for target sizes from 4 to 12 cm defining three beam geometries: single beam, opposed beam and orthogonal beam configurations. The two treatment planning systems currently employed in clinical practice were used, providing the NIRS-based and LEM-based GyE calculations. Physical dose distributions of NIRS-based and LEM-based treatment plans were compared. LEM-based prescription doses that minimize differences in physical dose distributions between the two systems were found. These doses were compared with the mean RBE-weighted dose obtained with a Monte Carlo code (FLUKA) interfaced with LEM I. In the investigated dose range, LEM-based RBE-weighted prescription doses, that minimize differences with NIRS plans, should be higher than NIRS reported prescription doses. The optimal dose depends on target size, shape and position, number of beams and dose level. The opposed beam configuration resulted in the smallest average prescription dose difference (0.45 ± 0.09 GyE). The second approach of recalculating NIRS RBE-weighted dose with a Monte Carlo code interfaced with LEM resulted in no significant difference with the results obtained from the planning study. The delivery of a voxel by voxel iso-effective plan, if different RBE models are employed, is not feasible; it is however possible to minimize differences in a treatment plan with the simple approach presented here. Dose prescription ultimately represents a clinical task under the responsibility of the radiation oncologist, the presented analysis intends to be a quantitative and objective way to assist the clinical decision.
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http://dx.doi.org/10.1088/0031-9155/57/22/7543DOI Listing
November 2012
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