30 years of ocular proton therapy, the Nice view.

PURPOSE: Radiotherapy with protons (PT) is a standard treatment of ocular tumors. It achieves excellent tumor control, limited toxicities, and the preservation of important functional outcomes, such as vision. Although PT may appear as one homogenous technique, it can be performed using dedicated ocular passive scattering PT or, increasingly, Pencil Beam Scanning (PBS), both with various degrees of patient-oriented customization. MATERAIAL AND METHODS: MEDICYC PT facility of Nice are detailed with respect to their technical, dosimetric, microdosimetric and radiobiological, patient and tumor-customization process of PT planning and delivery that are key. 6684 patients have been treated for ocular tumors (1991-2020). Machine characteristics (accelerator, beam line, beam monitoring) allow efficient proton extraction, high dose rate, sharp lateral and distal penumbrae, and limited stray radiation in comparison to beam energy reduction and subsequent straggling with high-energy PBS PT. Patient preparation before PT includes customized setup and image-guidance, CT-based planning, and ocular PT software modelling of the patient eye with integration of beam modifiers. Clinical reports have shown excellent tumor control rates (∼95%), vision preservation and limited toxicity rates (papillopathy, retinopathy, neovascular glaucoma, dry eye, madarosis, cataract). RESULTS: Although demanding, dedicated ocular PT has proven its efficiency in achieving excellent tumor control, OAR sparing and patient radioprotection. It is therefore worth adaptations of the equipments and practice. CONCLUSIONS: Some of these adaptations can be transferred to other PT centers and should be acknowledeged when using non-PT options.

Ocular proton therapy, pencil beam scanning high energy proton therapy or stereotactic radiotherapy for uveal melanoma; an in silico study.

PURPOSE: In radiotherapy, the dose and volumes of the irradiated normal tissues is correlated to the complication rate. We assessed the performances of low-energy proton therapy (ocular PT) with eye-dedicated equipment, high energy PT with pencil-beam scanning (PBS) or CyberKnifeR  -based stereotactic irradiation (SBRT). MATERIAL AND METHODS: CT-based comparative dose distribution between external beam radiotherapy techniques was assessed using an anthropomorphic head phantom. The prescribed dose was 60Gy_RBE in 4 fractions to a typical posterior pole uveal melanoma. Clinically relevant structures were delineated, and doses were calculated using radiotherapy treatment planning softwares and measured using Gafchromic dosimetry films inserted at the ocular level. RESULTS: Precision was significantly better with ocular PT than both PBS or SBRT in terms of beam penumbra (80%-20%: laterally 1.4 vs. ≥10mm, distally 0.8 vs. ≥2.5mm). Ocular PT duration was shorter, allowing eye gating and lid sparing more easily. Tumor was excellent with all modalities, but ocular PT resulted in more homogenous and conformal dose compared to PBS or SBRT. The maximal dose to ocular/orbital structures at risk was smaller and often null with ocular PT compared to other modalities. Mean dose to ocular/orbital structures was also lower with ocular PT. Structures like the lids and lacrimal punctum could be preserved with ocular PT using gaze orientation and lid retractors, which is easier to implement clinically than with the other modalities. The dose to distant organs was null with ocular PT and PBS, in contrast to SBRT. CONCLUSIONS: ocular PT showed significantly improved beam penumbra, shorter treatment delivery time, better dose homogeneity, and reduced maximal/mean doses to critical ocular structures compared with other current external beam radiation modalities. Similar comparisons may be warranted for other tumor presentations.

A 60 MeV proton beam-line dedicated to research and development programs.

A new proton beam-line dedicated to R&D programs has been developed at CentreAntoine Lacassagne (CAL), in Nice (France), in collaboration with the Centrenational d'études spatiales (CNES). This is the second beam-line of the MEDICYC 65 MeV cyclotron that is currently in operation, the first being the clinical 'eye-line' used for ocular proton therapy. The R&D beam-line is proposed with two configurations, the first producing a Gaussian narrow beam of a few mm width, the second a 100 mm diameter flat beam with a homogeneity better than ±3%. The energy range is (20 - ∼60) MeV, where the exact upper limit depends on the beam configuration being used. The energy spread of the non-degraded beam is (0.3 ± 0.1) MeV. A beam current between 10 pA and 10 µA can be produced with a stability better than 0.2% above 100 pA, and 2% below. The beam can be monitored online at a precision better than 5% in the flux range 1E5 (1E6) - 1E9 (1E10) p/cm2/s for a flat (Gaussian) configuration, although work is in progress to extend this range. Targeted applications for the R&D beam-line are instrumentation research, radiation tolerance tests of components and radiobiology.

[Proton imaging applications for proton therapy: state of the art]. / Imagerie protonique pour la protonthérapie : état de l'art.

Proton therapy allows a highly precise tumour volume irradiation with a low dose delivered to the healthy tissues. The steep dose gradients observed and the high treatment conformity require a precise knowledge of the proton range in matter and the target volume position relative to the beam. Thus, proton imaging allows an improvement of the treatment accuracy, and thereby, in treatment quality. Initially suggested in 1963, radiographic imaging with proton is still not used in clinical routine. The principal difficulty is the lack of spatial resolution, induced by the multiple Coulomb scattering of protons with nuclei. Moreover, its realization for all clinical locations requires relatively high energies that are previously not considered for clinical routine. Abandoned for some time in favor of X-ray technologies, research into new imaging methods using protons is back in the news because of the increase of proton radiation therapy centers in the world. This article exhibits a non-exhaustive state of the art in proton imaging.

Management of choroidal metastases.

BACKGROUND: Choroidal metastases (CM) are the most common malignant intraocular lesion observed in up to 4-12% of necropsy series of patients with solid cancer. The spectrum of presentations varies from prevalent CM in disseminated cancer to isolated CM. CM are responsible for visual deterioration. Depending on the primary cancer, estimated life expectancy, overall cancer presentation and ocular symptoms, the management of CM varies widely. We address the multidisciplinary management of CM and technical aspects of radiotherapy. MATERIAL AND METHODS: A systematic review of literature was performed from 1974 to 2014. RESULTS: Choroidal metastases occur preferentially in breast and lung carcinomas but are reported in all cancer types. The standard treatment remains external beam radiotherapy, applying 30Gy in 10 fractions or 40Gy in 20 fractions. The reported complete response and improved visual acuity rates are 80% and 57% to 89%, respectively. Some chemotherapy or new targeted therapy regimens yield promising CM response rates. DISCUSSION: Radiation therapy consistently shows rapid symptom alleviation, yield excellent local control and functional outcomes. However, there are only few reports on late toxicities after 6months given the unfavorable prognostic of CM patients. Selected patients may live more than two years, underlying the need to better assess mean and long term outcomes. Some authors have favored exclusive systemic strategies with omission of irradiation. The current literature suffers from the scarcity of prospective trials. Duration of tumor response following systemic therapy is rarely reported but appears less favorable as compared to radiotherapy. Systemic treatments may be proposed for pauci-symptomatic CM in a polymetastatic context while radiation therapy remains necessary in symptomatic CM either upfront or as an alternating treatment. Focalized radiation like brachytherapy and proton therapy may be proposed for isolated CM with long disease-free interval between primary and CM, as these techniques have the potential to yield better tumor and functional outcomes in patients with long life expectancy.

An indirect in vivo dosimetry system for ocular proton therapy.

Secondary radiation, particularly neutron radiation, is a cause of concern in proton therapy. However, one can take advantage of its presence by using it to retrieve useful information on the primary proton beam. At the Centre Antoine Lacassagne the secondary radiation in the treatment room has been studied in function of the beam modulation. A strong correlation was found between the secondary ambient dose equivalent per proton dose H*(10)/D and proton dose rate D/MU. A large volume ionisation chamber fixed on the wall at 2.5 m from the nozzle was used with an in-house computer interface to retrieve the value of D/MU derived from the measurement of photon H*(10) integrated over treatment time, using the correlation curve. This system enables the verification of D and D/MU to be made independently of the monitoring of the primary beam and represents a first step towards an alternative in vivo dosimetry in proton therapy.

Quantification of dose perturbations induced by external and internal accessories in ocular proton therapy and evaluation of their dosimetric impact.

PURPOSE: Proton scattering on beam shaping devices and protons slowing down on media with different densities within the treatment volume may produce dose perturbations and range variations that are not predicted by treatment planning systems. The aim of this work was to assess the dosimetric impact of elements present in ocular proton therapy treatments that may disturb the prescribed treatment plan. Both distal beam shaping devices and intraocular elements were considered. METHODS: A wedge filter, tantalum fiducial marker, hemispherical compensator, two intraocular endotamponades (densities 0.97 and 1.92 g cm(-3)) and an intraocular eye lens (IOL) were considered in the study. For these elements, longitudinal dose distributions were measured and∕or calculated in water in beam alignment for a clinical spread-out Bragg peak. Under the same conditions, the unperturbed dose distributions were similarly measured and∕or calculated in the absence of the element. The dosimetric impact was assessed by comparison of unperturbed and perturbed dose distributions. Measurements and calculations were carried out with two methods. Measurements are based on EBT3 films with dedicated software, which makes use of a calibration curve and correction for the quenching effect. Calculations are based on the Monte Carlo (MC) code MCNPX and reproduce the experimental conditions. Both dose maps are obtained with a resolution of 300 dpi. RESULTS: The degree of disturbance of distal beam shaping devices is low for the wedge filter (2% overdose ripple all along the central axis) and moderate for the hemispherical compensator (two bands of variable overdose of up to 10% downstream the compensator lateral edges and -5% underdose on the plateau at off-axis distance of 5 cm). Tantalum clips produce important dose shadows (-20% behind the clip parallel to the beam and range reduction of 1.1 mm) and bands of overdose (15%). The presence of endotamponades modifies the dose distribution very significantly (-5% underdose on the plateau and 3 mm range prolongation for the tamponade with density 0.97 g cm(-3) and -15% underdose on plateau and 8 mm range reduction for that with density 1.92 g cm(-3)). No dose perturbations were found for the IOL. The high performance of EBT3 film and MC tools used was confirmed and good agreement was found between them (percentage of pixels passing the gamma test >87%). CONCLUSIONS: The degree of disturbance by external beam shaping devices remains low in ocular proton therapy and can be reduced by bringing accessories closer to the eye. Tantalum fiducial markers must be located in such a way that dose perturbation is not projected on the tumor. The treatment of patients with intraocular endotamponades must be carefully managed. It is fundamental that radiation oncologists and medical physicists are informed about the presence of such substances prior to the treatment.

Study of the secondary neutral radiation in proton therapy: toward an indirect in vivo dosimetry.

PURPOSE: Secondary particles produced in the collision of protons with beam modifiers are of concern in proton therapy. Nevertheless, secondary radiation can provide information on the dosimetric parameters through its dependency on the modulating accessories (range shifter and range modulating wheel). Relatively little data have been reported in the literature for low-energy proton beams. The present study aims at characterizing the neutron and photon secondary radiation at the low-energy proton therapy facility of the Centre Antoine Lacassagne (CAL), and studying their correlation to the dosimetric parameters to explore possible practical uses of secondary radiation in the treatment quality for proton therapy. METHODS: The Monte Carlo code MCNPX was used to simulate the proton therapy facility at CAL. Neutron and photon fluence, Φ, and ambient dose equivalent per proton dose, H∗(10)∕D, were determined across the horizontal main plane spanning the whole treatment room. H∗(10)∕D was also calculated at two positions of the treatment room where dosimetric measurements were performed for validation of the Monte Carlo calculations. Calculations and measurements were extended to 100 clinical spread-out Bragg Peaks (SOBPs) covering the whole range of therapeutic dose rates (D∕MU) employed at CAL. In addition, the values of D and MU were also calculated for each SOBP and the results analyzed to study the relationship between secondary radiation and dosimetric parameters. RESULTS: The largest production of the secondary particles takes place at the modulating devices and the brass collimators located along the optical bench. Along the beam line and off the beam axis to 2.5 m away, H∗(10)∕D values ranged from 5.4 µSv∕Gy to 5.3 mSv∕Gy for neutrons, and were 1 order of magnitude lower for photons. H∗(10)∕D varied greatly with the distance and angle to the beam axis. A variation of a factor of 5 was found for the different range of modulations (SOBPs). The ratios between calculations and measurements were 2.3 and 0.5 for neutrons and photons, respectively, and remained constant for all the range of SOBPs studied, which provided validation for the Monte Carlo calculations. H∗(10)∕D values were found to correlate to the proton dose rate D∕MU with a power fit, both for neutrons and photons. This result was exploited to implement a system to obtain D∕MU values from the measurement of the integrated photon ambient dose equivalent H∗(10) during treatment, which provides a method to control the dosimetric parameters D∕MU and D. CONCLUSIONS: The treatment room at CAL is moderately polluted by secondary particles. The constant ratio between measurements and calculations for all SOBPs showed that simulations correctly predict the dosimetric parameters and the dependence of the production of secondary particles on the modulation. The correlation between H∗(10)∕D and D∕MU is a useful tool for quality control and is currently used at CAL. This system works as an indirect in vivo dosimetry method, which is so far not feasible in proton therapy. This tool requires very simple instrumentation and can be implemented from the measurement of either photons or neutrons.

Radiochromic EBT2 film dosimetry for low-energy protontherapy.

PURPOSE: In protontherapy, accessories are used in order to adapt the beam to the surface and to the depth of the target. They are positioned close to the patient in order to avoid perturbation effects related to proton scattering. The level of contamination of the beam caused by these accessories may be assessed by examining the dose maps in parallel planes to the beam incidence. The EBT2 radiochromic film is a suitable tool for this task, as it can be cut into small pieces and immersed in water. Prior to use the EBT2 film for dose measurements, its response when exposed to a proton beam must be analysed. METHODS: The measurements were performed at the Centre Antoine Lacassagne, using the hospital-based MEDICYC isochronous cyclotron which provides 65 MeV protons. Monoenergetic as well as polyenergetic beams were used. Small pieces of EBT2 films were irradiated with proton beams in a small water phantom. Films were exposed at various angles close to the beam incidence and received doses ranging from 0.25 to 500 Gy. The optical density (OD) was studied as a function of angle, dose and linear energy transfer (LET). RESULTS: The effective atomic number of the active layer of the film is close to that of water which prevents disturbances of the measurement. However, the high density and the significant thickness of the Mylar substrate surrounding the active layer affect the use of the film in a parallel orientation to the beam. Therefore, the substrate layer may totally or partially slow down the protons. The measurement is then no longer representative to what happens in water. The measurement errors can be corrected by applying a tilt angle of at least 5° between the film and the beam. The dose analysis reveals that the green channel is the most sensitive in the dose range from 1 to 100 Gy. The OD is accurately described by a Weibull function of the dose with four free parameters. The Weibull function is valid for both monoenergetic and polyenergetic beams if the LET is limited to values below 15 MeV g(- 1) cm(2). When using a film orientation close to the beam incidence angle, increasing LET values are encountered throughout the film axis gradually with the protons slowing down in water. The EBT2 films show an underestimated response for higher LET values. The comparison of data from the present study to data obtained by other authors for EBT films allows modelling the underestimated response as a function of the LET. The definition improvement of the link between OD and LET requires to integrate more closely the beam energy characteristics. CONCLUSIONS: The EBT2 film is a suitable dosimeter for analysing dose plans in planes nearly parallel to the beam orientation by compensating the underestimated dose response due to LET.

[Pacemaker, implanted cardiac defibrillator and irradiation: Management proposal in 2010 depending on the type of cardiac stimulator and prognosis and location of cancer]. / Pacemaker, défibrillateur et radiothérapie : propositions de conduite à tenir en 2010 en fonction du type de stimulateur cardiaque, du pronostic et du site du cancer.

Ionizing radiation may interfere with electric components of pacemakers or implantable cardioverter-defibrillators. The type, severity and extent of radiation damage to pacemakers, have previously been shown to depend on the total dose and dose rate. Over 300,000 new cancer cases are treated yearly in France, among which 60% are irradiated in the course of their disease. One among 400 of these patients has an implanted pacemaker or defibrillator. The incidence of pacemaker and implanted cardioverter defribillator increases in an ageing population. The oncologic prognosis must be weighted against the cardiologic prognosis in a multidisciplinary and transversal setting. Innovative irradiation techniques and technological sophistications of pacemakers and implantable cardioverter-defibrillators (with the introduction of more radiosensitive complementary metal-oxide-semiconductors since 1970) have potentially changed the tolerance profiles. This review of the literature studied the geometric, dosimetric and radiobiological characteristics of the radiation beams for high energy photons, stereotactic irradiation, protontherapy. Standardized protocols and radiotherapy optimization (particle, treatment fields, energy) are advisable in order to improve patient management during radiotherapy and prolonged monitoring is necessary following radiation therapy. The dose received at the pacemaker/heart should be calculated. The threshold for the cumulated dose to the pacemaker/implantable cardioverter-defibrillator (2 to 5 Gy depending on the brand), the necessity to remove/displace the device based on the dose-volume histogram on dosimetry, as well as the use of lead shielding and magnet are discussed.

[Cyberknife robotic stereotactic radiotherapy: technical aspects and recent developments]. / La radiothérapie stéréotaxique avec Cyberknife (R) : aspects pratiques et développements technologiques récents.

Cyberknife (Accuray Inc. Sunnyvale, USA) stereotactic body radiation therapy (SBRT) involves the delivery of a small number of large doses of radiation to a target volume using continuously evolving advanced technology. It has emerged as a novel treatment modality for cancer and modified some concepts of cancer treatment. It is indicated in early-stage primary cancer, sometimes as an alternative to surgery. It is also indicated for patients with oligometastatic disease who have relatively long survival with the aim to optimize disease control with a good quality of life. Although there remain some uncertainties regarding the radiobiology of hypofractionation, local control and tolerance have been promising. Indications are increasing under strict quality assurance programs worldwide and prospective clinical evaluation.

Innovative image-guided CyberKnife stereotactic radiotherapy for bladder cancer.

CyberKnife stereotactic body radiation therapy is used to treat extracranial tumour sites that move with respiration. It has also been employed for the successful treatment of prostate cancer, using the image-tracking CyberKnife system to compensate for intrafraction movements resulting from peristaltic motion and bladder filling. Large sporadic motions can be compensated for using an online target motion monitoring and cybernetic correction strategy. Radio-opaque gold markers can be implanted in the bladder during transurethral resection and used for online image-tracking during radiation to compensate for bladder filling and target movements. Transurethral bladder resection followed by chemoradiation and a stereotactic CyberKnife radiotherapy boost seems a promising approach for the treatment of invasive bladder cancer in heavily pre-treated patients or patients eligible for preservation strategies. In this case study of a patient with a previously irradiated pelvis, CyberKnife radiotherapy was feasible and well tolerated, with disease control and non-altered functional results two years after treatment completion. CyberKnife irradiation may also be considered for the conservative treatment of locally advanced T2-T4a N(0) M(0) bladder cancer with incomplete or uncertain transurethral resection.

[Current indications and ongoing clinical trials with CyberKnife stereotactic radiotherapy in France in 2009]. / Indications du CyberKnife et essais cliniques en cours en 2009.

Image-guided frameless fractionated stereotactic radiotherapy can be performed with millimetric accuracy using the CyberKnife (Accuray Inc. Sunnyvale, USA) equipped with an integrated tracking system for intra- and extracranial lesions. Highly conformal hypofractionated irradiation has been used to treat lesions with curative or palliative intent. It is advantageous for radioresistant tumors, re-irradiating lesions, boosting small volumes and treating tumors that move with respiration. It also limits travel costs and improves the quality of life. Over 60,000 patients have been treated worldwide using CyberKnife including 600 patients in the three French cancer centres of Nice, Nancy and Lille. These expert Cyberknife centres follow quality assurance programs and work together with the "Haute Autorité de santé" and the French National Cancer Institute (INCa) to promote clinical developments. The CyberKnife has been used to treat intracranial lesions including (but not limited to) meningiomas, acoustic schwannomas, brain oligometastases, as well as skull base tumors like chordomas, or para- or intraspinal tumors, and extracranial tumors such as lung cancers. Currently, extracranial stereotactic radiotherapy is particularly attractive for tumors moving with respiration and is being evaluated in liver, prostate and re-irradiation including head and neck tumors.

[CyberKnife robotic stereotactic radiotherapy: technical aspects and medical indications]. / Radiothérapie stéréotaxique robotisée par CyberKnife : aspects techniques et indications.

In 2006, 3 sites have been selected by the Institut national of cancer (Lille, Nancy et Nice) to evaluate a radiotherapy robot, the CyberKnife. This machine, able to track mobile tumours in real time, gives new possibilities in the field of extra cranial stereotactic radiotherapy. Functionalities and medico economical issues of the machine will be evaluated during 2 years on the 3 sites.