L. Raffaele

A 62 MeV proton beam for the treatment of ocular melanoma at Laboratori Nazionali del Sud-INFN (CATANIA)

At the INFN Laboratori Nazionali del Sud in Catania (Italy) the first Italian protontherapy facility, named CATANA (Centre di AdroTerapia e Applicazioni Nucleari Avanzate) has been realized in collaboration with the University of Catania. It is based on the use of the 62 MeV proton beam delivered by the K = 800 superconducting cyclotron installed and working at LNS since 1995. The facility is mainly devoted to the treatment of ocular diseases like uveal melanoma. A beam treatment line in air has been realized together with a dedicated positioning patient system. The facility is in operation since the beginning of 2002 and 52 patients have been successfully treated up to now. The main features of CATANA together with the clinical and dosimetric features will be extensively reported; particularly, will be described the proton beam line, that has been entirely realized at LNS, with all its elements, the experimental transversal and depth dose distributions of the 62 MeV proton beam obtained for a final collimator of 25 mm diameter and the experimental depth dose distributions of a modulated proton beam obtained for the same final collimator. Finally, the clinical results over one year of treatments, describing the features of the treated diseases will be reported.

Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy

Due to their ballistic precision, apoptosis induction by protons could be a strategy to specifically eliminate neoplastic cells. To characterize the cellular and molecular effects of these hadrons, we performed dose-response and time-course experiments by exposing different cell lines (PC3, Ca301D, MCF7) to increasing doses of protons and examining them with FACS, RT-PCR, and electron spin resonance (ESR). Irradiation with a dose of 10 Gy of a 26,7 Mev proton beam altered cell structures such as membranes, caused DNA double strand breaks, and significantly increased intracellular levels of hydroxyl ions, are active oxygen species (ROS). This modified the transcriptome of irradiated cells, activated the mitochondrial (intrinsic) pathway of apoptosis, and resulted in cycle arrest at the G2/M boundary. The number of necrotic cells within the irradiated cell population did not significantly increase with respect to the controls. The effects of irradiation with 20 Gy were qualitatively as well as quantitatively similar, but exposure to 40 Gy caused massive necrosis. Similar experiments with photons demonstrated that they induce apoptosis in a significantly lower number of cells and in a temporally delayed manner. These data advance our knowledge on the cellular and molecular effects of proton irradiation and could be useful for improving current hadrontherapy protocols.

Radiochromic film dosimetry of a low energy proton beam.

In this work some dosimetric characteristics of MD-55-2 GafChromic films were studied in a low energy proton beam (21.5 MeV) directly in a water phantom. The nonlinearity of the optical density was quantified by a factor P(lin). A correction factor P(en), that accounts for optical density dependence on the energy, was empirically determined. The effects of detector thickness in depth dose measurements and of the film orientation with respect to beam direction were investigated. The results show that the MD-55-2 films provide dose measurements with the films positioned perpendicularly to the proton beam. A dosimetric formalizm is proposed to determine the dose to water at depth d, with films oriented perpendicularly to the beam axis. This formalism uses a calibration factor of the radiochromic film determined directly on the proton beam at a reference depth in water, and the P(lin) factor, that takes into account the nonlinearity of the calibration curve and the P(en) factor that, in turn takes into account the change of proton beam energy in water. The MD-55-2 films with their high spatial resolution and the quasiwater equivalent material are attractive, positioned perpendicularly along the beam axis, for the absolute dose determination of very small beam sizes and modulated proton beams.

Clinical application of proton beams in the treatment of uveal melanoma: the first therapies carried out in Italy and preliminary results (CATANA Project).

Background The first Italian proton therapy facility was realized in Catania, at the INFN-LNS. With its energy (62 MeV proton beam), it is ideal for the treatment of shallow tumors like those of the ocular region: uveal melanoma, first of all (the most common primary intraocular malignancy of adults) and other less frequent lesions like choroidal hemangioma, conjunctiva melanoma, and eyelid tumors. Material and methods The first patient was enrolled in February 2002, and to date 30 patients have been treated. All patients had a localized uveal melanoma, with no systemic metastases, and had specific indications for proton beam radiation therapy: lesions between 5–25 mm basal diameter, not exceeding 15 mm thickness, absence of total retinal detachment or glaucoma. According to the tumor dimensions, 2 patients had a small lesion or T1 (6%), 3 had a medium-sized lesion or T2 (10%), 14 had a large lesion or T3 (47%), and 11 had an extra-large lesion or T3 (37%); no patient had extrascleral invasion or T4 of the TNM-AJCC Staging System. In most cases, the tumor infiltrated only the choroid (14 patients, 47%) or the choroid plus the ciliary body (14 patients, 47%). We also treated a primitive iris melanoma, without diffusion to the ciliary body. The target volume was defined as the tumor plus a safety margin of 2.5 mm, laterally and antero-posteriorly; this margin was increased to 3 mm if ciliary body involvement was present. The treatment was carried out in 4 fractions on 4 consecutive days to a total dose of 54.5 Gy (single fraction 13.6 Gy), which corresponds to 60 CGE (Cobalt Gray Equivalent; single fraction 15 CGE), because the relative biological effectiveness is 1.1. Results The first follow-up is planned at 6–8 months after the end of the treatment, and our clinical end points are local control (defined as cessation of growth or tumor shrinkage), eye retention, and maintenance of a good visual function. At the time of this writing, we had preliminary results from 13 patients. Nine patients showed tumor shrinkage (69%), 3 a substantially stable dimension (23%), but almost all patients presented an increased ultrasound reflectivity (a surrogate for tumor control). Discussion and conclusions The literature data show that charged particle therapy has allowed an optimal local control in the treatment of uveal melanomas (about 96% in the different series, superior to that obtained with plaquetherapy [between 83% and 92%]), a metastatic rate slightly better than enucleation reports, and a survival rate of almost 90% at 5 years. Our preliminary results show a tumor response in almost all cases, with no major acute or subacute side effects. We thus plan to continue with our treatment procedures and our dose prescription.

Dosimetric characterization of a microDiamond detector in clinical scanned carbon ion beams.

PURPOSE To investigate for the first time the dosimetric properties of a new commercial synthetic diamond detector (PTW microDiamond) in high-energy scanned clinical carbon ion beams generated by a synchrotron at the CNAO facility. METHODS The detector response was evaluated in a water phantom with actively scanned carbon ion beams ranging from 115 to 380 MeV/u (30-250 mm Bragg peak depth in water). Homogeneous square fields of 3 × 3 and 6 × 6 cm(2) were used. Short- and medium-term (2 months) detector response stability, dependence on beam energy as well as ion type (carbon ions and protons), linearity with dose, and directional and dose-rate dependence were investigated. The depth dose curve of a 280 MeV/u carbon ion beam, scanned over a 3 × 3 cm(2) area, was measured with the microDiamond detector and compared to that measured using a PTW Advanced Markus ionization chamber, and also simulated using fluka Monte Carlo code. The detector response in two spread-out-Bragg-peaks (SOBPs), respectively, centered at 9 and 21 cm depths in water and calculated using the treatment planning system (TPS) used at CNAO, was measured. RESULTS A negligible drift of detector sensitivity within the experimental session was seen, indicating that no detector preirradiation was needed. Short-term response reproducibility around 1% (1 standard deviation) was found. Only 2% maximum variation of microDiamond sensitivity was observed among all the evaluated proton and carbon ion beam energies. The detector response showed a good linear behavior. Detector sensitivity was found to be dose-rate independent, with a variation below 1.3% in the evaluated dose-rate range. A very good agreement between measured and simulated Bragg curves with both microDiamond and Advanced Markus chamber was found, showing a negligible LET dependence of the tested detector. A depth dose curve was also measured by positioning the microDiamond with its main axis oriented orthogonally to the beam direction. A strong distortion in Bragg peak measurement was observed, confirming manufacturer recommendation on avoiding such configuration. Very good results were obtained for SOBP measurements, with a difference below 1% between measured and TPS-calculated doses. The stability of detector sensitivity in the observation period was within the experimental uncertainty. CONCLUSIONS Dosimetric characterization of a PTW microDiamond detector in high-energy scanned carbon ion beams was performed. The results of the present study showed that this detector is suitable for dosimetry of clinical carbon ion beams, with a negligible LET and dose-rate dependence.

Response of a Human Melanoma Cell Line to Low and High Ionizing Radiation

Abstract:  Effects of single irradiation with gamma rays and protons on human HTB140 melanoma cell growth were compared. Exponentially growing cells were irradiated close to the Bragg peak maximum of the unmodulated 62 MeV protons, as well as with 60Co gamma rays. Applied doses ranged from 8 to 24 Gy. Viability of cells and proliferation capacity were assessed 7 days after irradiation. Induction of apoptosis and cell cycle phase redistribution were observed 6 and 48 h after irradiation. Significant inhibitory effects of both irradiation qualities were detected 7 days after irradiation. Important reduction of HTB140 cell viability was observed after irradiation with protons. Almost linear and highly significant (P < 0.001) decrease of cell proliferation was observed 7 days after irradiation with gamma rays and protons, as compared to nonirradiated controls. Protons induced apoptosis, both 6 and 48 h after irradiation. With the increase of post‐irradiation incubation time, number of apoptotic cells decreased. Exposure of HTB140 cells to gamma rays did not provoke apoptotic cell death. Important number of cells in G1‐S phase, detected by the cell cycle phase redistribution analyses, suggested high metabolic activity of irradiated melanoma cells within the first 48 h. Both irradiation qualities caused modest G2‐M arrest 6 and 48 h after irradiation, thus supporting results that illustrated high radioresistance of HTB140 cells.

Locally advanced rectal cancer: Qualitative and quantitative evaluation of diffusion-weighted MR imaging in the response assessment after neoadjuvant chemo-radiotherapy

Purpose to investigate the added value of qualitative and quantitative evaluation of diffusion weighted (DW) magnetic resonance (MR) imaging in response assessment after neoadjuvant chemo-radiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Methods 31 patients with LARC (stage ≥ T3) were enrolled in the study. All patients underwent conventional MRI and DWI before starting therapy and after neoadjuvant CRT. All patients underwent surgery; pathologic staging represented the reference standard. For qualitative analysis, two radiologists retrospectively reviewed conventional MR images and the combined set of conventional and DW MR images and recorded their confidence level with respect to complete response (ypCR). For quantitative analysis, tumor’s apparent diffusion coefficient (ADC) values were measured at each examination. ADC pre-CRT, ADC post-CRT and Δ ADC post−ADC pre of the three groups of response (ypCR, partial response ypPR, stable disease ypSD) were compared. Receiver-operating characteristics (ROC) curve analysis was employed to investigate the discriminatory capability for ypCR, responders (ypCR, ypPR) and ypSD of each measure. Results addition of DWI to conventional T2-weighted sequences improved diagnostic performance of MRI in the evaluation of ypCR. A low tumor ADC value in the pre-CRT examination, a high ADC value in the post-CRT examination, a high Δ ADC post−ADC pre [>0.3 (×10−3 mm2/s)] were predictive of ypCR. Conclusions DW sequences improve MR capability to evaluate tumor response to CRT. Nevertheless, no functional MR technique alone seems accurate enough to safely select patients with ypCR.

Preliminary investigation on the use of the MOSFET dosimeter in proton beams

Metal Oxide Semiconductor (MOS) device structures can be used to measure ionizing radiation through the mechanism of hole trapping in the oxide layer leading to changing of electrical characteristic of the device. They are a new type of direct reading semiconductor dosimeters. Due to their extremely small physical size, ability to permanently store the accumulated dose, dose-rate independence and their ease of use make them very promising for in vivo dosimetry. They are attractive for dosimetry in small radiation fields used in modern radiation oncology modalities, as conformal radiotherapy, IMRT, stereotactic radiotherapy/radiosurgery and proton therapy. Preliminary results on the use of commercial MOSFET dosimeters (TN-502RD, Thomson & Nielsen Electronics Ltd, Canada) irradiated on therapeutic 62 MeV proton beams are presented. Linearity with absorbed dose, sensibility and energy dependence were investigated. Moreover, the possibility to use of MOSFET dosimeters in order to measure the Output Factors (OF) for very small irradiation fields was verified. The comparison of OF obtained using MOSFETs and other dosimetry systems is reported.

ENERGY LOSS MEASUREMENTS OF 27 MEV PROTONS IRRADIATING WATER-EQUIVALENT MATERIALS

Abstract The use of proton beams represents one of the most innovative fields of application in Radiotherapy. The interest is growing up in considering the possibility offered by proton beams and, in general, by ions to increase the target dose while reducing the outside dose at healthy tissues. Clinical proton beam dosimetry represents a fundamental aspect to exploit the features of this therapy. In this paper we will report depth-dose measurements in equivalent tissue materials (polyethylene and polytetrafluoroethylene). A 27 MeV proton beam delivered by the LNS Tandem accelerator, a Markus ionization chamber and LiF-PTFE thermoluminescent disks were used to perform these investigations. Calculations of the delivered doses and the experimental set-up will be described in detail.

DoPET: an in-treatment monitoring system for proton therapy at 62 MeV

Proton beam radiotherapy is highly effective in treating cancer thanks to its conformal dose deposition. This superior capability in dose deposition has led to a massive growth of the treated patients around the world, raising the need of treatment monitoring systems. An in-treatment PET system, DoPET, was constructed and tested at CATANA beam-line, LNS-INFN in Catania, where 62 MeV protons are used to treat ocular melanoma. The PET technique profits from the beta+ emitters generated by the proton beam in the irradiated body, mainly 15-O and 11-C. The current DoPET prototype consists of two planar 15 cm × 15 cm LYSO-based detector heads. With respect to the previous versions, the system was enlarged and the DAQ up-graded during the years so now also anthropomorphic phantoms, can be fitted within the field of view of the system. To demonstrate the capability of DoPET to detect changes in the delivered treatment plan with respect to the planned one, various treatment plans were used delivering a standard 15 Gy fraction to an anthropomorphic phantom. Data were acquired during and after the treatment delivery up to 10 minutes. When the in-treatment phase was long enough (more than 1 minute), the corresponding activated volume was visible just after the treatment delivery, even if in presence of a noisy background. The after-treatment data, acquired for about 9 minutes, were segmented finding that few minutes are enough to be able to detect changes. These experiments will be presented together with the studies performed with PMMA phantoms where the DoPET response was characterized in terms of different dose rates and in presence of range shifters: the system response is linear up to 16.9 Gy/min and has the ability to see a 1 millimeter range shifter.