Nicolas Depauw

Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas.

Negative surgical margins are uncommon for spine sarcomas; hence, adjuvant radiotherapy (RT) may be recommended but tumor dose may be constrained by spinal cord, nerve, and viscera tolerance.

Assessment of out-of-field absorbed dose and equivalent dose in proton fields

PURPOSE In proton therapy, as in other forms of radiation therapy, scattered and secondary particles produce undesired dose outside the target volume that may increase the risk of radiation-induced secondary cancer and interact with electronic devices in the treatment room. The authors implement a Monte Carlo model of this dose deposited outside passively scattered fields and compare it to measurements, determine the out-of-field equivalent dose, and estimate the change in the dose if the same target volumes were treated with an active beam scanning technique. METHODS Measurements are done with a thimble ionization chamber and the Wellhofer MatriXX detector inside a Lucite phantom with field configurations based on the treatment of prostate cancer and medulloblastoma. The authors use a GEANT4 Monte Carlo simulation, demonstrated to agree well with measurements inside the primary field, to simulate fields delivered in the measurements. The partial contributions to the dose are separated in the simulation by particle type and origin. RESULTS The agreement between experiment and simulation in the out-of-field absorbed dose is within 30% at 10-20 cm from the field edge and 90% of the data agrees within 2 standard deviations. In passive scattering, the neutron contribution to the total dose dominates in the region downstream of the Bragg peak (65%-80% due to internally produced neutrons) and inside the phantom at distances more than 10-15 cm from the field edge. The equivalent doses using 10 for the neutron weighting factor at the entrance to the phantom and at 20 cm from the field edge are 2.2 and 2.6 mSv/Gy for the prostate cancer and cranial medulloblastoma fields, respectively. The equivalent dose at 15-20 cm from the field edge decreases with depth in passive scattering and increases with depth in active scanning. Therefore, active scanning has smaller out-of-field equivalent dose by factors of 30-45 in the entrance region and this factor decreases with depth. CONCLUSIONS The dose deposited immediately downstream of the primary field, in these cases, is dominated by internally produced neutrons; therefore, scattered and scanned fields may have similar risk of second cancer in this region. The authors confirm that there is a reduction in the out-of-field dose in active scanning but the effect decreases with depth. GEANT4 is suitable for simulating the dose deposited outside the primary field. The agreement with measurements is comparable to or better than the agreement reported for other implementations of Monte Carlo models. Depending on the position, the absorbed dose outside the primary field is dominated by contributions from primary protons that may or may not have scattered in the brass collimating devices. This is noteworthy as the quality factor of the low LET protons is well known and the relative dose risk in this region can thus be assessed accurately.

Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

PURPOSE To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). METHODS AND MATERIALS All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. RESULTS Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. CONCLUSIONS Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.

Monte Carlo study of the potential reduction in out-of-field dose using a patient-specific aperture in pencil beam scanning proton therapy

This study is aimed at identifying the potential benefits of using a patient-specific aperture in proton beam scanning. For this purpose, an accurate Monte Carlo model of the pencil beam scanning (PBS) proton therapy (PT) treatment head at Massachusetts General Hospital (MGH) was developed based on an existing model of the passive double-scattering (DS) system. The Monte Carlo code specifies the treatment head at MGH with sub-millimeter accuracy. The code was configured based on the results of experimental measurements performed at MGH. This model was then used to compare out-of-field doses in simulated DS treatments and PBS treatments. For the conditions explored, the penumbra in PBS is wider than in DS, leading to higher absorbed doses and equivalent doses adjacent to the primary field edge. For lateral distances greater than 10 cm from the field edge, the doses in PBS appear to be lower than those observed for DS. We found that placing a patient-specific aperture at nozzle exit during PBS treatments can potentially reduce doses lateral to the primary radiation field by over an order of magnitude. In conclusion, using a patient-specific aperture has the potential to further improve the normal tissue sparing capabilities of PBS.

Sensitivity study of proton radiography and comparison with kV and MV x-ray imaging using GEANT4 Monte Carlo simulations.

The imaging sensitivity of proton radiography has been studied and compared with kV and MV x-ray imaging using Monte Carlo simulations. A phantom was specifically modeled using 21 different material inserts with densities ranging from 0.001 to 1.92 g cm(-3). These simulations were run using the MGH double scattered proton beam, scanned pencil proton beams from 200 to 490 MeV, as well as pure 50 keV, 100 keV, 1 MeV and 2 MeV gamma x-ray beams. In order to compare the physics implied in both proton and photon radiography without being biased by the current state of the art in detector technology, the detectors were considered perfect. Along with spatial resolution, the contrast-to-noise ratio was evaluated and compared for each material. These analyses were performed using radiographic images that took into account the following: only primary protons, both primary and secondary protons, and both contributions while performing angular and energetic cuts. Additionally, tissue-to-tissue contrasts in an actual lung cancer patient case were studied for simulated proton radiographs and compared against the original kV x-ray image which corresponds to the current patient set-up image in the proton clinic. This study highlights the poorer spatial resolution of protons versus x-rays for radiographic imaging purposes, and the excellent density resolution of proton radiography. Contrasts around the tumor are higher using protons in a lung cancer patient case. The high-density resolution of proton radiography is of great importance for specific tumor diagnostics, such as in lung cancer, where x-ray radiography operates poorly. Furthermore, the use of daily proton radiography prior to proton therapy would ameliorate patient set-up while reducing the absorbed dose delivered through imaging.

Proof of principle study of the use of a CMOS active pixel sensor for proton radiography.

PURPOSE Proof of principle study of the use of a CMOS active pixel sensor (APS) in producing proton radiographic images using the proton beam at the Massachusetts General Hospital (MGH). METHODS A CMOS APS, previously tested for use in s-ray radiation therapy applications, was used for proton beam radiographic imaging at the MGH. Two different setups were used as a proof of principle that CMOS can be used as proton imaging device: (i) a pen with two metal screws to assess spatial resolution of the CMOS and (ii) a phantom with lung tissue, bone tissue, and water to assess tissue contrast of the CMOS. The sensor was then traversed by a double scattered monoenergetic proton beam at 117 MeV, and the energy deposition inside the detector was recorded to assess its energy response. Conventional x-ray images with similar setup at voltages of 70 kVp and proton images using commercial Gafchromic EBT 2 and Kodak X-Omat V films were also taken for comparison purposes. RESULTS Images were successfully acquired and compared to x-ray kVp and proton EBT2/X-Omat film images. The spatial resolution of the CMOS detector image is subjectively comparable to the EBT2 and Kodak X-Omat V film images obtained at the same object-detector distance. X-rays have apparent higher spatial resolution than the CMOS. However, further studies with different commercial films using proton beam irradiation demonstrate that the distance of the detector to the object is important to the amount of proton scatter contributing to the proton image. Proton images obtained with films at different distances from the source indicate that proton scatter significantly affects the CMOS image quality. CONCLUSION Proton radiographic images were successfully acquired at MGH using a CMOS active pixel sensor detector. The CMOS demonstrated spatial resolution subjectively comparable to films at the same object-detector distance. Further work will be done in order to establish the spatial and energy resolution of the CMOS detector for protons. The development and use of CMOS in proton radiography could allow in vivo proton range checks, patient setup QA, and real-time tumor tracking.

A novel approach to postmastectomy radiation therapy using scanned proton beams.

PURPOSE Postmastectomy radiation therapy (PMRT), currently offered at Massachusetts General Hospital, uses proton pencil beam scanning (PBS) with intensity modulation, achieving complete target coverage of the chest wall and all nodal regions and reduced dose to the cardiac structures. This work presents the current methodology for such treatment and the ongoing effort for its improvements. METHODS AND MATERIALS A single PBS field is optimized to ensure appropriate target coverage and heart/lung sparing, using an in-house-developed proton planning system with the capability of multicriteria optimization. The dose to the chest wall skin is controlled as a separate objective in the optimization. Surface imaging is used for setup because it is a suitable surrogate for superficial target volumes. In order to minimize the effect of beam range uncertainties, the relative proton stopping power ratio of the material in breast implants was determined through separate measurements. Phantom measurements were also made to validate the accuracy of skin dose calculation in the treatment planning system. Additionally, the treatment planning robustness was evaluated relative to setup perturbations and patient breathing motion. RESULTS PBS PMRT planning resulted in appropriate target coverage and organ sparing, comparable to treatments by passive scattering (PS) beams but much improved in nodal coverage and cardiac sparing compared to conventional treatments by photon/electron beams. The overall treatment time was much shorter than PS and also shorter than conventional photon/electron treatment. The accuracy of the skin dose calculation by the planning system was within ±2%. The treatment was shown to be adequately robust relative to both setup uncertainties and patient breathing motion, resulting in clinically satisfying dose distributions. CONCLUSIONS More than 25 PMRT patients have been successfully treated at Massachusetts General Hospital by using single-PBS fields. The methodology and robustness of both the setup and the treatment have been discussed.

Characterizing the modulation transfer function (MTF) of proton/carbon radiography using Monte Carlo simulations

PURPOSE To characterize the modulation transfer function (MTF) of proton/carbon radiography using Monte Carlo simulations. To assess the spatial resolution of proton/carbon radiographic imaging. METHODS A phantom was specifically modeled with inserts composed of two materials with three different densities of bone and lung. The basic geometry of the phantom consists of cube-shaped inserts placed in water. The thickness of the water, the thickness of the cubes, the depth of the cubes in the water, and the particle beam energy have all been varied and studied. There were two phantom thicknesses considered 20 and 28 cm. This represents an average patient thickness and a thicker sized patient. Radiographs were produced for proton beams at 230 and 330 MeV and for a carbon ion beam at 400 MeV per nucleon. The contrast-to-noise ratio (CNR) was evaluated at the interface of two materials on the radiographs, i.e., lung-water and bone-water. The variation in CNR at interface between lung-water and bone-water were study, where a sigmoidal fit was performed between the lower and the higher CNR values. The full width half-maximum (FWHM) value was then obtained from the sigmoidal fit. Ultimately, spatial resolution was defined by the 10% point of the modulation-transfer-function (MTF10%), in units of line-pairs per mm (lp/mm). RESULTS For the 20 cm thick phantom, the FWHM values varied between 0.5 and 0.7 mm at the lung-water and bone-water interfaces, for the proton beam energies of 230 and 330 MeV and the 400 MeV/n carbon beam. For the 28 cm thick phantom, the FWHM values varied between 0.5 and 1.2 mm at the lung-water and bone-water interface for the same inserts and beam energies. For the 20 cm phantom the MTF10% for lung-water interface is 2.3, 2.4, and 2.8 lp/mm, respectively, for 230, 330, and 400 MeV/n beams. For the same 20 cm thick phantom but for the bone-water interface the MTF10% yielded 1.9, 2.3, and 2.7 lp/mm, respectively, for 230, 330, and 400 MeV/n beams. In the case of the thicker 28 cm phantom, the authors observed that at the lung-water interface the MTF10% is 1.6, 1.9, and 2.6 lp/mm, respectively, for 230, 330, and 400 MeV/n beams. While for the bone-water interface the MTF10% was 1.4, 1.9, and 2.9 lp/mm, respectively, for 230, 330, and 400 MeV/n beams. CONCLUSIONS Carbon radiography (400 MeV/n) yielded best spatial resolution, with MTF10% = 2.7 and 2.8 lp/mm, respectively, at the lung-water and bone-water interfaces. The spatial resolution of the 330 MeV proton beam was better than the 230 MeV proton, because higher incident proton energy suffer smaller deflections within the patient and thus yields better proton radiographic images. The authors also observed that submillimeter resolution can be obtained with both proton and carbon beams.

Impact of Spot Size and Beam-Shaping Devices on the Treatment Plan Quality for Pencil Beam Scanning Proton Therapy

PURPOSE This study aimed to assess the clinical impact of spot size and the addition of apertures and range compensators on the treatment quality of pencil beam scanning (PBS) proton therapy and to define when PBS could improve on passive scattering proton therapy (PSPT). METHODS AND MATERIALS The patient cohort included 14 pediatric patients treated with PSPT. Six PBS plans were created and optimized for each patient using 3 spot sizes (∼12-, 5.4-, and 2.5-mm median sigma at isocenter for 90- to 230-MeV range) and adding apertures and compensators to plans with the 2 larger spots. Conformity and homogeneity indices, dose-volume histogram parameters, equivalent uniform dose (EUD), normal tissue complication probability (NTCP), and integral dose were quantified and compared with the respective PSPT plans. RESULTS The results clearly indicated that PBS with the largest spots does not necessarily offer a dosimetric or clinical advantage over PSPT. With comparable target coverage, the mean dose (Dmean) to healthy organs was on average 6.3% larger than PSPT when using this spot size. However, adding apertures to plans with large spots improved the treatment quality by decreasing the average Dmean and EUD by up to 8.6% and 3.2% of the prescribed dose, respectively. Decreasing the spot size further improved all plans, lowering the average Dmean and EUD by up to 11.6% and 10.9% compared with PSPT, respectively, and eliminated the need for beam-shaping devices. The NTCP decreased with spot size and addition of apertures, with maximum reduction of 5.4% relative to PSPT. CONCLUSIONS The added benefit of using PBS strongly depends on the delivery configurations. Facilities limited to large spot sizes (>∼8 mm median sigma at isocenter) are recommended to use apertures to reduce treatment-related toxicities, at least for complex and/or small tumors.

Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries

The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in- and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields.