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To adopt Monte Carlo (MC) simulations as an independent dose calculation method for proton pencil beam radiotherapy, an interface that converts the plan information in DICOM format into MC components such as geometries and beam source is a crucial element. For this purpose, a DICOM-RT Ion interface (https://github.com/topasmc/dicom-interface) has been developed and integrated into the TOPAS MC code to perform such conversions on-the-fly. DICOM-RT objects utilized in this interface include Ion Plan (RTIP), Ion Beams Treatment Record (RTIBTR), CT image, and Dose. Beamline geometries, gantry and patient coordinate systems, and fluence maps are determined from RTIP and/or RTIBTR. In this interface, DICOM information is processed and delivered to a MC engine in two steps. A MC model, which consists of beamline geometries and beam source, to represent a treatment machine is created by a DICOM parser of the interface. The complexities from different DICOM types, various beamline configurations and source models are handled in this step. Next, geometry information and beam source are transferred to TOPAS on-the-fly via the developed TOPAS extensions. This interface with two treatment machines was successfully deployed into our automated MC workflow which provides simulated dose and LET distributions in a patient or a water phantom automatically when a new plan is identified. The developed interface provides novel features such as handling multiple treatment systems based on different DICOM types, DICOM conversions on-the-fly, and flexible sampling methods that significantly reduce the burden of handling DICOM based plan or treatment record information for MC simulations.

Purpose Treatment planning for proton therapy requires the relative proton stopping power ratio (RSP) information of the patient for accurate dose calculations. RSP are conventionally obtained after mapping of the Hounsfield units (HU) from a calibrated patient computed tomography (CT). One or multiple CT are needed for a given treatment which represents additional, undesired dose to the patient. For prostate cancer, magnetic resonance imaging (MRI) scans are the gold standard for segmentation while offering dose-less imaging. We here quantify the clinical applicability of converted MR images as a substitute for intensity modulated proton therapy (IMPT) treatment of the prostate. Methods MRCAT (Magnetic Resonance for Calculating ATtenuation) is a Philips-developed technology which produces a synthetic CT image consisting of five HU from a specific set of MRI acquisitions. MRCAT and original planning CT data sets were obtained for ten patients. An IMPT plan was generated on the MRCAT for each patient. Plans were produced such that they fulfill the prostate protocol in use at Massachusetts General Hospital (MGH). The plans were then recomputed onto the nominal planning CT for each patient. Robustness analyses (±5 mm setup shifts and ±3.5 % range uncertainties) were also performed. Results Comparison of MRCAT plans and their recomputation onto the planning CT plan showed excellent agreement. Likewise, dose perturbations due to setup shifts and range uncertainties were well within clinical acceptance demonstrating the clinical viability of the approach. Conclusions This work demonstrate the clinical acceptability of substituting MR converted RSP images instead of CT for IMPT planning of prostate cancer. This further translates into higher contouring accuracy along with lesser imaging dose.

Purpose/objective(s) Patients with node-positive (LN+) uterine or cervical cancer often require adjuvant radiation to the pelvis and para-aortics, resulting in significant acute and late gastrointestinal (GI) and genitourinary (GU) toxicity. Proton therapy allows for more conformal delivery of radiation dose. The objective was to prospectively evaluate the safety and efficacy of proton beam radiation therapy (RT) for patients with LN+ uterine or cervical cancer requiring RT. Materials/methods Patients with IIIC uterine and pT1,2N1M0 cervical cancer status post hysterectomy and lymphadenectomy were eligible. Sequential (uterine) and concurrent (cervical) chemotherapy were allowed. Exclusion criteria included life expectancy Results 21 patients completed RT between 10/2013 and 10/2018. Median follow-up is 52.3 months (range, 11.2-63.4). Median age was 59.7 years (range, 31.5-79.2). 15 patients had IIIC uterine cancer (13 endometrioid) and 6 patients had cervical cancer. 52% received sequential and 29% received concurrent chemotherapy. Median dose was 45.0 Gy (RBE). 20 (95%) received VB boost. 4 received PRT and 17 EFRT. Acute grade 2 and 3 GI toxicity was 24% and 14%, respectively. Acute grade 2 and 3 GU toxicity was 10% and 0%, respectively. Acute grade 2 and 3 hematologic toxicity was 24% and 0%, respectively. To date, there have been no late toxicities > grade 3. The 2-year PFS was 81% (95% CI, 56%-92%). Of the 5 patients that recurred, 4 were peritoneal and 1 was abdominal wall and lung; no recurrences were in-field. The 2-year OS was 86% (95% CI, 62%-95%). Conclusion Scanned proton beam RT appears effective in preventing local-regional recurrence in LN+ patients with uterine and cervical cancer undergoing adjuvant radiation. Acute toxicity is low and severe late effects have not been observed but await longer follow-up. Author disclosure A.L. Russo: None. K.D. Bernstein: None. S.P. Nisbet: None. N. Horick: None. N. Depauw: None. B.Y. Yeap: None. H.M. Kooy: None. T.F. DeLaney: None. A.H. Russell: None.

Purpose Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. Methods and Materials Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. Results The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. Conclusions Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

Purpose/Objective(s) Our institution developed proton stereotactic radiosurgery (PSRS) techniques and treated patients since 1961. A recent upgrade from passive scattering (PS) delivery to pencil beam scanning (PBS) required validation of this modality for small fields. We describe the adaptation of an existing clinical PSRS service to PBS. We outline potential advantages and disadvantages the modality has to offer. Materials/Methods Patient alignment is determined from 2D/3D x-ray corrections of surgically implanted fiducials. End-to-end tests using a skull phantom were performed to validate a change of treatment planning system (TPS). PSRS PS fields from prior years established applicable parameters for dose, range, modulation, field size and aspect ratio for PBS validation. 18 fields were created to verify agreement with the TPS. A diamond detector was used to measure SOBP doses and film to measure profiles. A QA phantom enabled simultaneous measurement with film and diamond detector. X-rays were used to verify detector alignment prior to measurements. A hybrid 2D/3D γ-analysis was used to assess lateral profiles. Plans were generated for previously treated patients and used to perform end-to-end tests. These included 6 AVM, 3 pituitaries and 1 cavernous sinus lesion. Clinical directives were obtained from the original plans. Results End-to-end phantom tests conformed sub-mm alignment. Distal and proximal depth agreement were 0.10 ± 0.66% and 0.74 ± 0.48 mm. Isocenter and shallow depth dose agreement was -1.7 ± 2.9% and 2.5 ± 5.1%, respectively. Global 2%/1mm/10% γ-analysis resulted in pass rates of 97.2 ± 4.8%. 24 clinical fields were delivered. Dose agreement was -2.8 ± 2.7%. Global 3%/1mm/10% γ- analysis PASS rates were 99.5 ± 1.4%. Conclusion We have revalidated SRS appropriate fiducial-based alignment and defined a small-field QA process using a diamond detector & film to demonstrate PSRS performed with PBS delivery is accurate. Proton delivery systems and TPS modeling can differ significantly. Therefore, validation and plan quality results should not be generalized to all systems. Proton range uncertainties play an important role in determining the appropriateness of PSRS. PBS does not offer distal benefits for small targets compared to passive scattering using range compensators. Larger SRS targets with irregular shapes may benefit from intensity variations and variable modulation offered by PBS. VMAT generally provides slightly superior target coverage for small pituitary lesion, but target coverage for larger pituitary lesions not abutting the optic structures and prescribed to lower doses are more comparable for VMAT and PBS while lowering integral dose. Our validation effort enabled the transition of an active PSRS program from PS to PBS. Author Disclosure M. Bussiere: None. J. Daartz: None. J. Verburg: Employee; Massachusetts General Hospital. Research Grant; National Cancer Institute. N. Depauw: None. H.M. Kooy: None. J.S. Loeffler: Employee; Massachusetts General Hospital. Advisory Board; Mevion. P.H. Chapman: None. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital.

Background Spot charge is one parameter of pencil-beam scanning dose delivery system whose accuracy is typically high but whose required value has not been investigated. In this work we quantify the dose impact of spot charge inaccuracies on the dose distribution in patients. Knowing the effect of charge errors is relevant for conventional proton machines, as well as for new generation proton machines, where ensuring accurate charge may be challenging. Methods Through perturbation of spot charge in treatment plans for 7 patients and a phantom, we evaluated the dose impact of absolute (up to 5 X 106 protons) and relative (up to 30%) charge errors. We investigated the dependence on beam width by studying scenarios with small, medium and large beam sizes. Treatment plan statistics included the Ƭ passing rate, dose-volume-histograms and dose differences. Results The allowable absolute charge error for small spot plans was about 2×106 protons. Larger limits would be allowed if larger spots were used. For relative errors, the maximum allowable error size for small, medium and large spots was about 13%, 8% and 6% for small, medium and large spots, respectively. Conclusions Dose distributions turned out to be surprisingly robust against random spot charge perturbation. Our study suggests that ensuring spot charge errors as small as 1-2% as is commonly aimed at in conventional proton therapy machines, is clinically not strictly needed. This article is protected by copyright. All rights reserved.

Purpose At present, proton craniospinal irradiation (CSI) for growing children is delivered to the whole vertebral body (WVB) to avoid asymmetric growth. We aimed to demonstrate the feasibility and potential clinical benefit of delivering vertebral body sparing (VBS) versus WVB CSI with passively scattered (PS) and intensity modulated proton therapy (IMPT) in growing children treated for medulloblastoma. Methods and Materials Five plans were generated for medulloblastoma patients, who had been previously treated with CSI PS proton radiation therapy: ( 1 ) single posteroanterior (PA) PS field covering the WVB (PS-PA-WVB); ( 2 ) single PA PS field that included only the thecal sac in the target volume (PS-PA-VBS); ( 3 ) single PA IMPT field covering the WVB (IMPT-PA-WVB); ( 4 ) single PA IMPT field, target volume including thecal sac only (IMPT-PA-VBS); and ( 5 ) 2 posterior-oblique (−35°, +35°) IMPT fields, with the target volume including the thecal sac only (IMPT2F-VBS). For all cases, 23.4 Gy (relative biologic effectiveness [RBE]) was prescribed to 95% of the spinal canal. The dose, linear energy transfer, and variable-RBE-weighted dose distributions were calculated for all plans using the tool for particle simulation, version 2, Monte Carlo system. Results IMPT VBS techniques efficiently spared the anterior vertebral bodies (AVBs), even when accounting for potential higher variable RBE predicted by linear energy transfer distributions. Assuming an RBE of 1.1, the V10 Gy(RBE) decreased from 100% for the WVB techniques to 59.5% to 76.8% for the cervical, 29.9% to 34.6% for the thoracic, and 20.6% to 25.1% for the lumbar AVBs, and the V20 Gy(RBE) decreased from 99.0% to 17.8% to 20.0% for the cervical, 7.2% to 7.6% for the thoracic, and 4.0% to 4.6% for the lumbar AVBs when IMPT VBS techniques were applied. The corresponding percentages for the PS VBS technique were higher. Conclusions Advanced proton techniques can sufficiently reduce the dose to the vertebral body and allow for vertebral column growth for children with central nervous system tumors requiring CSI. This was true even when considering variable RBE values. A clinical trial is planned for VBS to the thoracic and lumbosacral spine in growing children.

Setup and range uncertainties compromise radiotherapy plan robustness. We introduce a method to evaluate the clinical effect of these uncertainties on the population using tumor control probability (TCP) and normal tissue complication probability (NTCP) models. Eighteen oropharyngeal cancer patients treated with curative intent were retrospectively included. Both photon (VMAT) and proton (IMPT) plans were created using a planning target volume as planning objective. Plans were recalculated for uncertainty scenarios: two for range over/undershoot (IMPT) or CT-density scaling (VMAT), six for shifts. An average shift scenario ([Formula: see text]) was calculated to assess random errors. Dose differences between nominal and scenarios were translated to TCP (2 models) and NTCP (15 models). A weighted average (W_Avg) of the TCP\NTCP based on Gaussian distribution over the variance scenarios was calculated to assess the clinical effect of systematic errors on the population. TCP/NTCP uncertainties were larger in IMPT compared to VMAT. Although individual perturbations showed risks of plan deterioration, the [Formula: see text] scenario did not show a substantial decrease in any of the TCP endpoints suggesting evaluated plans in this cohort were robust for random errors. Evaluation of the W_Avg scenario to assess systematic errors showed in VMAT no substantial decrease in TCP endpoints and in IMPT a limited decrease. In IMPT, the W_Avg scenario had a mean TCP loss of 0%-2% depending on plan type and primary or nodal control. The W_Avg for NTCP endpoints was around 0%, except for mandible necrosis in IMPT (W_Avg: 3%). The estimated population impact of setup and range uncertainties on TCP/NTCP following VMAT or IMPT of oropharyngeal cancer patients was small for both treatment modalities. The use of TCP/NTCP models allows for clinical interpretation of the population effect and could be considered for incorporation in robust evaluation methods. Highlights: - TCP/NTCP models allow for a clinical evaluation of uncertainty scenarios. - For this cohort, in silico-PTV based IMPT plans and VMAT plans were robust for random setup errors. - Effect of systematic errors on the population was limited: mean TCP loss was 0%-2%.

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 (D mean ) 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 D mean 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 D mean 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.

Background In scanned proton beam therapy systematic deviations in spot size at iso-center can occur as a result of changes in the beam-line optics. There is currently no general guideline of the spot size accuracy required clinically. In this work we quantify treatment plan robustness to systematic spot size variations as a function of spot size and spot spacing, and we suggest guidelines for tolerance levels for spot size variations. Methods Through perturbation of spot size in treatment plans for 7 patients and a phantom, we evaluated the dose impact of systematic spot size variations of 5% up to 50%. We investigated the dependence on nominal spot size by studying scenarios with small, medium and large spot sizes for various inter-spot spacings. To come to tolerance levels, we used the Γ passing rate and dose-volume-histograms. Results Limits on spot size accuracy were extracted for 8 sites, 3 different spot sizes and 3 different inter-spot spacings. While the allowable spot size variation strongly depends on the spot size, the inter-spot spacing turned out to be only of limited influence. Conclusions Plan robustness to spot size variations strongly depend on spot size, with small spot plans being much more robust than larger spots plans. Inter-spot spacing did not influence plan robustness. Combining our results with existing literature, we propose limits of ±25%, ±20% and ±10% of the spot width σ , for spots with σ of 2.5, 5.0 and 10 mm in proton therapy spot scanning facilities, respectively.

Purpose: To shorten delivery times of intensity modulated proton therapy by reducing the number of energy layers in the treatment plan. Methods and Materials: We have developed an energy layer reduction method, which was implemented into our in-house-developed multicriteria treatment planning system "Erasmus-iCycle." The method consisted of 2 components: (1) minimizing the logarithm of the total spot weight per energy layer; and (2) iteratively excluding low-weighted energy layers. The method was benchmarked by comparing a robust "time-efficient plan" (with energy layer reduction) with a robust "standard clinical plan" (without energy layer reduction) for 5 oropharyngeal cases and 5 prostate cases. Both plans of each patient had equal robust plan quality, because the worst-case dose parameters of the standard clinical plan were used as dose constraints for the time-efficient plan. Worst-case robust optimization was performed, accounting for setup errors of 3 mm and range errors of 3% + 1 mm. We evaluated the number of energy layers and the expected delivery time per fraction, assuming 30 seconds per beam direction, 10 ms per spot, and 400 Giga-protons per minute. The energy switching time was varied from 0.1 to 5 seconds. Results: The number of energy layers was on average reduced by 45% (range, 30%-56%) for the oropharyngeal cases and by 28% (range, 25%-32%) for the prostate cases. When assuming 1, 2, or 5 seconds energy switching time, the average delivery time was shortened from 3.9 to 3.0 minutes (25%), 6.0 to 4.2 minutes (32%), or 12.3 to 7.7 minutes (38%) for the oropharyngeal cases, and from 3.4 to 2.9 minutes (16%), 5.2 to 4.2 minutes (20%), or 10.6 to 8.0 minutes (24%) for the prostate cases. Conclusions: Delivery times of intensity modulated proton therapy can be reduced substantially without compromising robust plan quality. Shorter delivery times are likely to reduce treatment uncertainties and costs. (C) 2015 Elsevier Inc. All rights reserved.

The differences between planning proton-beam therapy and photon-beam therapy derive from the differences in the physics of protons and photons, namely [1]: That protons have a finite and controllable (through choice of energy) penetration in depth with virtually no exit dose (Fig. 3.1). That the penetration of protons is strongly affected by the nature (e.g., density) of the tissues through which they pass, while photons are much less affected (density changes generally give rise to only small intensity changes, except for the lung). Therefore, heterogeneities are much more important in proton-beam therapy than in photon-beam therapy (Fig. 3.2). The apparatus for proton-beam delivery is different, and its details affect the dose distributions (Chap. 2).

Purpose: Patient specific apertures are commonly employed in passive double scattering (DS) proton therapy (PT). This study was aimed at identifying the potential benefits of using such an aperture in pencil beam scanning (PBS). Methods: An accurate Geant4 Monte Carlo model of the PBS 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 and 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. The PBS treatments were simulated both with and without the patient‐specific aperture used in the DS treatment.Results: For the conditions explored, a typical prostate field, the lateral 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 10cm from the field edge, the doses in PBS appear to be lower than those observed for DS. Including an aperture at nozzle exit reduces the penumbral width by preventing wide‐angle scatter from reaching the patient. This can reduce the dose in PBS for lateral distances of less than 10cm from the field edge by over an order of magnitude and allow better dose conformity. Conclusions: 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. This has the potential to further improve the normal tissue sparing capabilities of PBS. The magnitude of this effect depends on the beam spot size of the scanning system and is thus facility dependent.

Purpose This work aims to characterise a proton pencil-beam scanning (PBS) and passive double scattering (DS) systems as well as to measure parameters relevant to the relative biological effectiveness (RBE) of the beam using a silicon-on-insulator (SOI) microdosimeter with well-defined 3D sensitive volumes (SV). The dose equivalent downstream and laterally outside of a clinical PBS treatment field was assessed and compared to that of a DS beam. Methods A novel silicon microdosimeter with well-defined 3D SVs was used in this study. It was connected to low noise electronics, allowing for detection of lineal energies as low as 0.15 keV/μm. The microdosimeter was placed at various depths in a water phantom along the central axis of the proton beam, and at the distal part of the spread out Bragg peak (SOBP) in 0.5 mm increments. The RBE values of the pristine Bragg peak (BP) and SOBP were derived using the measured microdosimetric lineal energy spectra as inputs to the modified microdosimetric kinetic model (MKM). Geant4 simulations were performed in order to verify the calculated depth-dose distribution from the treatment planning system (TPS) and to compare the simulated dose-mean lineal energy to the experimental results. Results For a 131 MeV PBS spot (124.6 mm R90 range in water), the measured dose-mean lineal energy yD¯, increased from 2 keV/μm at the entrance to 8 keV/μm in the BP, with a maximum value of 10 keV/μm at the distal edge. The derived RBE distribution for the PBS beam slowly increased from 0.97 ± 0.14 at the entrance to 1.04 ± 0.09 proximal to the BP, then to 1.1 ± 0.08 in the BP, and steeply rose to 1.57 ± 0.19 at the distal part of the BP. The RBE distribution for the DS SOBP beam was approximately 0.96 ± 0.16 to 1.01 ± 0.16 at shallow depths, and 1.01 ± 0.16 to 1.28 ± 0.17 within the SOBP. The RBE significantly increased from 1.29 ± 0.17 to 1.43 ± 0.18 at the distal edge of the SOBP. Conclusions The SOI microdosimeter with its well-defined 3D SV has applicability in characterising proton radiation fields and can measure relevant physical parameters to model the RBE with sub-millimetre spatial resolution. It has been shown that for a physical dose of 1.82 Gy at the BP, the derived RBE based on the MKM model increased from 1.14 to 1.6 in the BP and its distal part. Good agreement was observed between the experimental and simulation results, confirming the potential application of SOI microdosimeter with 3D SV for quality assurance in proton therapy. This article is protected by copyright. All rights reserved.

Purpose Proton radiation therapy is commonly used in young children with brain tumors for its potential to reduce late effects. However, some proton series report higher rates of brainstem injury (0%-16%) than most photon series (2.2%-8.6%). We report the incidence of brainstem injury and a risk factor analysis in pediatric patients with posterior fossa primary tumors treated with proton radiation therapy at our institution. Methods and Materials The study included 216 consecutive patients treated between 2000 and 2015. Dosimetry was available for all but 4 patients. Grade 2 to 5 late brainstem toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Results The histologies include medulloblastoma (n=154, 71.3%), ependymoma (n=56, 25.9%), and atypical teratoid rhabdoid tumor (n=6, 2.8%). The median age at irradiation was 6.6 years (range, 0.5-23.1 years); median dose, 54 gray relative biological effectiveness (Gy RBE) (range, 46.8-59.4 Gy RBE); and median follow-up period, 4.2 years (range, 0.1-15.3 years) among 198 survivors. Of the patients, 83.3% received chemotherapy; 70.4% achieved gross total resection. The crude rate of injury was 2.3% in all patients, 1.9% in those with medulloblastoma, 3.6% in those with ependymoma, and 0% in those with atypical teratoid rhabdoid tumor. The 5-year cumulative incidence of injury was 2.0% (95% confidence interval, 0.7%-4.8%). The median brainstem dose (minimum dose received by 50% of brainstem) in the whole cohort was 53.6 Gy RBE (range, 16.5-56.8 Gy RBE); maximum point dose within the brainstem (Dmax), 55.2 Gy RBE (range, 48.4-60.5 Gy RBE); and mean dose, 50.4 Gy RBE (range, 21.1-56.7 Gy RBE). In the 5 patients with injury, the median minimum dose received by 50% of the brainstem was 54.6 Gy RBE (range, 50.2-55.1 Gy RBE); Dmax, 56.2 Gy RBE (range, 55.0-57.1 Gy RBE); mean dose, 51.3 Gy RBE (range, 45.4-54.4 Gy RBE); and median volume of the brainstem receiving ≥55 Gy RBE (V55), 27.4% (range, 0%-59.4%). Of the 5 patients with injury, 4 had a brainstem Dmax in the highest quartile (≥55.8 Gy RBE, P = .016) and a V55 in the highest tertile (>6.0%) of the cohort distribution (P = .047). Of the 5 patients with injury, 3 were aged >6 years (age range, 4.1-22.8 years), and 4 of 5 patients received chemotherapy and achieved gross total resection. Conclusions The incidence of injury in pediatric patients with posterior fossa tumors is consistent with previous reports in the photon setting. Our data suggest that when Dmax and V55 are kept

Background Spot size σ (in air at isocenter), interspot spacing d, and spot charge q influence dose delivery efficiency and plan quality in Intensity Modulated Proton Therapy (IMPT) treatment planning. The choice and range of parameters varies among different manufacturers. The goal of this work is to demonstrate the influence of the spot parameters on dose quality and delivery in IMPT treatment plans, to show their interdependence, and to make practitioners aware of the spot parameter values for a certain facility. Our study could help as a guideline to make the trade-off between treatment quality and time in existing PBS centers and in future systems. Methods We created plans for seven patients and a phantom, with different tumor sites and volumes, and compared the effect of small-, medium-, and large-spot widths (σ = 2.5, 5, and 10 mm) and interspot distances (1σ, 1.5σ, and 1.75σ) on dose, spot charge, and treatment time. Moreover, we quantified how postplanning charge threshold cuts affect plan quality and the total number of spots to deliver, for different spot widths and interspot distances. We show the effect of a minimum charge (or MU) cutoff value for a given proton delivery system. Results Spot size had a strong influence on dose: larger spots resulted in more protons delivered outside the target region. We observed dose differences of 2–13 Gy (RBE) between 2.5 mm and 10 mm spots, where the amount of extra dose was due to dose penumbra around the target region. Interspot distance had little influence on dose quality for our patient group. Both parameters strongly influence spot charge in the plans and thus the possible impact of postplanning charge threshold cuts. If such charge thresholds are not included in the treatment planning system (TPS), it is important that the practitioner validates that a given combination of lower charge threshold, interspot spacing, and spot size does not result in a plan degradation. Low average spot charge occurs for small spots, small interspot distances, many beam directions, and low fractional dose values. Conclusions The choice of spot parameters values is a trade-off between accelerator and beam line design, plan quality, and treatment efficiency. We recommend the use of small spot sizes for better organ-at-risk sparing and lateral interspot distances of 1.5σ to avoid long treatment times. We note that plan quality is influenced by the charge cutoff. Our results show that the charge cutoff can be sufficiently large (i.e., 106 protons) to accommodate limitations on beam delivery systems. It is, therefore, not necessary per se to include the charge cutoff in the treatment planning optimization such that Pareto navigation (e.g., as practiced at our institution) is not excluded and optimal plans can be obtained without, perhaps, a bias from the charge cutoff. We recommend that the impact of a minimum charge cut impact is carefully verified for the spot sizes and spot distances applied or that it is accommodated in the TPS.

Purpose Setup, range, and anatomical uncertainties influence the dose delivered with intensity modulated proton therapy (IMPT), but clinical quantification of these errors for oropharyngeal cancer is lacking. We quantified these factors and investigated treatment fidelity, that is, robustness, as influenced by adaptive planning and by applying more beam directions. Methods and Materials We used an in-house treatment planning system with multicriteria optimization of pencil beam energies, directions, and weights to create treatment plans for 3-, 5-, and 7-beam directions for 10 oropharyngeal cancer patients. The dose prescription was a simultaneously integrated boost scheme, prescribing 66 Gy to primary tumor and positive neck levels (clinical target volume-66 Gy; CTV-66 Gy) and 54 Gy to elective neck levels (CTV-54 Gy). Doses were recalculated in 3700 simulations of setup, range, and anatomical uncertainties. Repeat computed tomography (CT) scans were used to evaluate an adaptive planning strategy using nonrigid registration for dose accumulation. Results For the recalculated 3-beam plans including all treatment uncertainty sources, only 69% (CTV-66 Gy) and 88% (CTV-54 Gy) of the simulations had a dose received by 98% of the target volume (D98%) >95% of the prescription dose. Doses to organs at risk (OARs) showed considerable spread around planned values. Causes for major deviations were mixed. Adaptive planning based on repeat imaging positively affected dose delivery accuracy: in the presence of the other errors, percentages of treatments with D98% >95% increased to 96% (CTV-66 Gy) and 100% (CTV-54 Gy). Plans with more beam directions were not more robust. Conclusions For oropharyngeal cancer patients, treatment uncertainties can result in significant differences between planned and delivered IMPT doses. Given the mixed causes for major deviations, we advise repeat diagnostic CT scans during treatment, recalculation of the dose, and if required, adaptive planning to improve adequate IMPT dose delivery.

Purpose To describe, in a setting of non-small cell lung cancer (NSCLC), the theoretical dosimetric advantages of proton arc stereotactic body radiation therapy (SBRT) in which the beam penumbra of a rotating beam is used to reduce the impact of range uncertainties. Methods and Materials Thirteen patients with early-stage NSCLC treated with proton SBRT underwent repeat planning with photon volumetric modulated arc therapy (Photon-VMAT) and an in-house-developed arc planning approach for both proton passive scattering (Passive-Arc) and intensity modulated proton therapy (IMPT-Arc). An arc was mimicked with a series of beams placed at 10° increments. Tumor and organ at risk doses were compared in the context of high- and low-dose regions, represented by volumes receiving >50% and Results In the high-dose region, conformality index values are 2.56, 1.91, 1.31, and 1.74, and homogeneity index values are 1.29, 1.22, 1.52, and 1.18, respectively, for 3 proton passive scattered beams, Passive-Arc, IMPT-Arc, and Photon-VMAT. Therefore, proton arc leads to a 30% reduction in the 95% isodose line volume to 3-beam proton plan, sparing surrounding organs, such as lung and chest wall. For chest wall, V30 is reduced from 21 cm 3 (3 proton beams) to 11.5 cm 3 , 12.9 cm 3 , and 8.63 cm 3 ( P =.005) for Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. In the low-dose region, the mean lung dose and V20 of the ipsilateral lung are 5.01 Gy(relative biological effectiveness [RBE]), 4.38 Gy(RBE), 4.91 Gy(RBE), and 5.99 Gy(RBE) and 9.5%, 7.5%, 9.0%, and 10.0%, respectively, for 3-beam, Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. Conclusions Stereotactic body radiation therapy with proton arc and Photon-VMAT generate significantly more conformal high-dose volumes than standard proton SBRT, without loss of coverage of the tumor and with significant sparing of nearby organs, such as chest wall. In addition, both proton arc approaches spare the healthy lung from low-dose radiation relative to photon VMAT. Our data suggest that IMPT-Arc should be developed for clinical use.

Purpose Dosimetric planning studies have described potential benefits for the use of proton radiation therapy (RT) for locally advanced breast cancer. We report acute toxicities and feasibility of proton delivery for 12 women treated with postmastectomy proton radiation with or without reconstruction. Methods and Materials Twelve patients were enrolled in an institutional review board-approved prospective clinical trial. The patients were assessed for skin toxicity, fatigue, and radiation pneumonitis during treatment and at 4 and 8 weeks after the completion of therapy. All patients consented to have photographs taken for documentation of skin toxicity. Results Eleven of 12 patients had left-sided breast cancer. One patient was treated for right-sided breast cancer with bilateral implants. Five women had permanent implants at the time of RT, and 7 did not have immediate reconstruction. All patients completed proton RT to a dose of 50.4 Gy (relative biological effectiveness [RBE]) to the chest wall and 45 to 50.4 Gy (RBE) to the regional lymphatics. No photon or electron component was used. The maximum skin toxicity during radiation was grade 2, according to the Common Terminology Criteria for Adverse Events (CTCAE). The maximum CTCAE fatigue was grade 3. There have been no cases of RT pneumonitis to date. Conclusions Proton RT for postmastectomy RT is feasible and well tolerated. This treatment may be warranted for selected patients with unfavorable cardiac anatomy, immediate reconstruction, or both that otherwise limits optimal RT delivery using standard methods.

Background and purpose Delivery of post-mastectomy radiation (PMRT) in women with bilateral implants represents a technical challenge, particularly when attempting to cover regional lymph nodes. Intensity modulated proton therapy (IMPT) holds the potential to improve dose delivery and spare non-target tissues. The purpose of this study was to compare IMPT to three-dimensional (3D) conformal radiation following bilateral mastectomy and reconstruction. Materials and methods Ten IMPT, 3D conformal photon/electron (P/E), and 3D photon (wide tangent) plans were created for 5 patients with breast cancer, all of whom had bilateral breast implants. Using RTOG guidelines, a physician delineated contours for both target volumes and organs-at-risk. Plans were designed to achieve 95% coverage of all targets (chest wall, IMN, SCV, axilla) to a dose of 50.4 Gy or Gy (RBE) while maximally sparing organs-at-risk. Results IMPT plans conferred similar target volume coverage with enhanced homogeneity. Both mean heart and lung doses using IMPT were significantly decreased compared to both P/E and wide tangent planning. Conclusions IMPT provides improved homogeneity to the chest wall and regional lymphatics in the post-mastectomy setting with improved sparing of surrounding normal structures for woman with reconstructed breasts. IMPT may enable women with mastectomy to undergo radiation therapy without the need for delay in breast reconstruction.

This study investigates whether 'pencil beam resampling', i.e. iterative selection and weight optimization of randomly placed pencil beams (PBs), reduces optimization time and improves plan quality for multi-criteria optimization in intensity-modulated proton therapy, compared with traditional modes in which PBs are distributed over a regular grid. Resampling consisted of repeatedly performing: (1) random selection of candidate PBs from a very fine grid, (2) inverse multi-criteria optimization, and (3) exclusion of low-weight PBs. The newly selected candidate PBs were added to the PBs in the existing solution, causing the solution to improve with each iteration. Resampling and traditional regular grid planning were implemented into our in-house developed multi-criteria treatment planning system 'Erasmus iCycle'. The system optimizes objectives successively according to their priorities as defined in the so-called 'wish-list'. For five head-and-neck cancer patients and two PB widths (3 and 6 mm sigma at 230 MeV), treatment plans were generated using: (1) resampling, (2) anisotropic regular grids and (3) isotropic regular grids, while using varying sample sizes (resampling) or grid spacings (regular grid). We assessed differences in optimization time (for comparable plan quality) and in plan quality parameters (for comparable optimization time). Resampling reduced optimization time by a factor of 2.8 and 5.6 on average (7.8 and 17.0 at maximum) compared with the use of anisotropic and isotropic grids, respectively. Doses to organs-at-risk were generally reduced when using resampling, with median dose reductions ranging from 0.0 to 3.0 Gy (maximum: 14.3 Gy, relative: 0%-42%) compared with anisotropic grids and from -0.3 to 2.6 Gy (maximum: 11.4 Gy, relative: -4%-19%) compared with isotropic grids. Resampling was especially effective when using thin PBs (3 mm sigma). Resampling plans contained on average fewer PBs, energy layers and protons than anisotropic grid plans and more energy layers and protons than isotropic grid plans. In conclusion, resampling resulted in improved plan quality and in considerable optimization time reduction compared with traditional regular grid planning.

The first proton radiotherapy patient was treated in 1957 at the Berkeley Radiation Laboratory. At the Harvard Cyclotron Laboratory, treatments commenced shortly after in the early 1960s under the direction of the Massachusetts General Hospital neurosurgeon Dr. Raymond Kjellberg. Neurosurgeons were well equipped to use the precision of proton beams without the availability of 3D imaging technologies such as CT. Their appreciation of the 3D cranial anatomy projected on X-rays sufficed to treat neoplasms such as pituitary abnormalities and arterial venous malformations. Both Dr. Kjellberg in Boston and Dr. Leksell in Stockholm pioneered the use of protons in the cranial anatomy. Dr. Kjellberg’s program, however, had ready access to the proton beam at the HCL (Fig. 7.1). Dr. Leksell’s program did not have ready access which led to the invention of the Leksell Gamma Knife as an alternative therapeutic system for stereotactic radiosurgery. Protons were thus the first modality used in cranial stereotactic radiosurgery, while the Gamma Knife made cranial stereotactic radiosurgery a standard modality.

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.

Purpose To report the early outcomes for children with high-risk neuroblastoma treated with proton radiotherapy (RT) and to compare the dose distributions for intensity-modulated photon RT (IMRT), three-dimensional conformal proton RT (3D-CPT), and intensity-modulated proton RT to the postoperative tumor bed. Methods and Materials All patients with high-risk (International Neuroblastoma Staging System Stage III or IV) neuroblastoma treated between 2005 and 2010 at our institution were included. All patients received induction chemotherapy, surgical resection of residual disease, high-dose chemotherapy with stem cell rescue, and adjuvant 3D-CPT to the primary tumor sites. The patients were followed with clinical examinations, imaging, and laboratory testing every 6 months to monitor disease control and side effects. IMRT, 3D-CPT, and intensity-modulated proton RT plans were generated and compared for a representative case of adjuvant RT to the primary tumor bed followed by a boost. Results Nine patients were treated with 3D-CPT. The median age at diagnosis was 2 years (range 10 months to 4 years), and all patients had Stage IV disease. All patients had unfavorable histologic characteristics (poorly differentiated histologic features in 8, N-Myc amplification in 6, and 1p/11q chromosomal abnormalities in 4). The median tumor size at diagnosis was 11.4 cm (range 7–16) in maximal dimension. At a median follow-up of 38 months (range 11–70), there were no local failures. Four patients developed distant failure, and, of these, two died of disease. Acute side effects included Grade 1 skin erythema in 5 patients and Grade 2 anorexia in 2 patients. Although comparable target coverage was achieved with all three modalities, proton therapy achieved substantial normal tissue sparing compared with IMRT. Intensity-modulated proton RT allowed additional sparing of the kidneys, lungs, and heart. Conclusions Preliminary outcomes reveal excellent local control with proton therapy for high-risk neuroblastoma, although distant failures continu to occur. Dosimetric comparisons demonstrate the advantage of proton RT compared with IMRT in this setting, allowing more conformal treatment and better normal tissue sparing.

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.

Proton, as well as other ion, beams applied by electro-magnetic deflection in pencil-beam scanning (PBS) are minimally perturbed and thus can be quantified a priori by their fundamental interactions in a medium. This a priori quantification permits an optimal reduction of characterizing measurements on a particular PBS delivery system. The combination of a priori quantification and measurements will then suffice to fully describe the physical interactions necessary for treatment planning purposes. We consider, for proton beams, these interactions and derive a 'Golden' beam data set. The Golden beam data set quantifies the pristine Bragg peak depth-dose distribution in terms of primary, multiple Coulomb scatter, and secondary, nuclear scatter, components. The set reduces the required measurements on a PBS delivery system to the measurement of energy spread and initial phase space as a function of energy. The depth doses are described in absolute units of Gy(RBE) mm² Gp⁻¹, where Gp equals 10⁹ (giga) protons, thus providing a direct mapping from treatment planning parameters to integrated beam current. We used these Golden beam data on our PBS delivery systems and demonstrated that they yield absolute dosimetry well within clinical tolerance.

Delivery of pencil beam scanning (PBS) requires the on-line measurement of several beam parameters. If the measurement is outside of specified tolerances and a binary threshold algorithm is used, the beam will be paused. Given instrumentation and statistical noise such a system can lead to many pauses which could increase the treatment time. Statistical quality control methods are typically used on manufacturing lines to monitor a process and give early detection of a gradual problem and stop the process if a deviation is statistically significant. These methods can be used to develop a more intuitive algorithm for (PBS) delivery systems that is robust and safe and leads to decreased treatment times. The Exponentially Weighted Moving Average (EWMA) control scheme monitors deviations in beam properties which are averaged over a specified number of measurements with greater weight applied to the more recent ones. Simulation of an EWMA-style algorithm safely detected shifts in random and systematic delivery errors without false alarms. Binary and EWMA methods can be combined for improved reliability without sacrificing patient safety. In the EWMA method, the mean of a beam property can be related to systematic uncertainties and the standard deviation can be related to random uncertainties. This method allows one to have separate interlock levels for each type of uncertainty and to detect systematic trends.

Purpose: To describe a fast projection algorithm for optimizing intensity modulated proton therapy (IMPT) plans and to describe and demonstrate the use of this algorithm in multicriteria IMPT planning. Methods: The authors develop a projection-based solver for a class of convex optimization problems and apply it to IMPT treatment planning. The speed of the solver permits its use in multicriteria optimization, where several optimizations are performed which span the space of possible treatment plans. The authors describe a plan database generation procedure which is customized to the requirements of the solver. The optimality precision of the solver can be specified by the user. Results: The authors apply the algorithm to three clinical cases: A pancreas case, an esophagus case, and a tumor along the rib cage case. Detailed analysis of the pancreas case shows that the algorithm is orders of magnitude faster than industry-standard general purpose algorithms (MOSEK’s interior point optimizer, primal simplex optimizer, and dual simplex optimizer). Additionally, the projection solver has almost no memory overhead. Conclusions: The speed and guaranteed accuracy of the algorithm make it suitable for use in multicriteria treatment planning, which requires the computation of several diverse treatment plans. Additionally, given the low memory overhead of the algorithm, the method can be extended to include multiple geometric instances and proton range possibilities, for robust optimization.

Pencil beam scanning (PBS) periodic quality assurance (QA) programs ensure the beam delivered to patients is within technical specifications. Two critical specifications for PBS delivery are the beam width and position. The aim of this study is to investigate whether a 2D ionization chamber array, such as the MatriXX detector (IBA Dosimetry, Schwarzenbruck, Germany), can be used to characterize submillimeter-sized PBS beam properties. The motivation is to use standard equipment, which may have pixel spacing coarser than the pencil beam size, and simplify QA workflow. The MatriXX pixels are cylindrical in shape with 4.5 mm diameter and are spaced 7.62 mm from center to center. Two major effects limit the ability of using the MatriXX to measure the spot position and width accurately. The first effect is that too few pixels sample the Gaussian shaped pencil beam profile and the second effect is volume averaging of the Gaussian profile over the pixel sensitive volumes. We designed a method that overcomes both limitations and hence enables the use of the MatriXX to characterize sub-millimeter-sized PBS beam properties. This method uses a cross-like irradiation pattern that is designed to increase the number of sampling data points and a modified Gaussian fitting technique to correct for volume averaging effects. Detector signals were calculated in this study and random noise and setup errors were added to simulate measured data. With the techniques developed in this work, the MatriXX detector can be used to characterize the position and width of sub-millimeter, σ = 0.7 mm, sized pencil beams with uncertainty better than 3% relative to σ. With the irradiation only covering 60% of the MatriXX, the position and width of σ = 0.9 mm sized pencil beams can be determined with uncertainty better than 3% relative to σ. If one were to not use a cross-like irradiation pattern, then the position and width of σ = 3.6 mm sized pencil beams can be determined with uncertainty better than 3% relative to σ. If one were to not use a cross-like pattern nor volume averaging corrections, then the position and width of σ = 5.0 mm sized pencil beams can be determined with uncertainty better than 3% relative to σ. This work helps to simplify periodic QA in proton therapy because more routinely used ionization chamber arrays can be used to characterize narrow pencil beam properties.

Proton radiation therapy has been available for decades. However, until recently it was only applied to a small number of patients at approximately 20 centers worldwide. Increased clinical experience with protons, as well as extensive research in the physics, biology and clinical aspects of proton therapy, have recently led to a huge interest in proton therapy among radiation oncologists. In addition, the cost for facilities is expected to decrease. Many proton therapy facilities are currently being built and planned worldwide. It is expected that the number of patients treated with protons will increase substantially in the near future. This article summarizes the rationale for (proton) radiation therapy and addresses the promises and challenges of proton-beam therapy in the management of localized cancer.

Purpose We completed an implementation of pencil-beam scanning (PBS), a technology whereby a focused beam of protons, of variable intensity and energy, is scanned over a plane perpendicular to the beam axis and in depth. The aim of radiotherapy is to improve the target to healthy tissue dose differential. We illustrate how PBS achieves this aim in a patient with a bulky tumor. Methods and Materials Our first deployment of PBS uses "broad" pencil-beams ranging from 20 to 35 mm (full-width-half-maximum) over the range interval from 32 to 7 g/cm 2 . Such beam-brushes offer a unique opportunity for treating bulky tumors. We present a case study of a large (4,295 cc clinical target volume) retroperitoneal sarcoma treated to 50.4 Gy relative biological effectiveness (RBE) (presurgery) using a course of photons and protons to the clinical target volume and a course of protons to the gross target volume. Results We describe our system and present the dosimetry for all courses and provide an interdosimetric comparison. Discussion The use of PBS for bulky targets reduces the complexity of treatment planning and delivery compared with collimated proton fields. In addition, PBS obviates, especially for cases as presented here, the significant cost incurred in the construction of field-specific hardware. PBS offers improved dose distributions, reduced treatment time, and reduced cost of treatment.

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 inmore » 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.« less

Proton radiotherapy centers that currently use passively scattered proton beams do field specific calibrations for a non-negligible fraction of treatment fields, which is time and resource consuming. Our improved understanding of the passive scattering mode of the IBA universal nozzle, especially of the current modulation function, allowed us to re-commission our treatment control system for accurate delivery of SOBPs of any range and modulation, and to predict the output for each of these fields. We moved away from individual field calibrations to a state where continued quality assurance of SOBP field delivery is ensured by limited system-wide measurements that only require one hour per week. This manuscript reports on a protocol for generation of desired SOBPs and prediction of dose output.

A mini-multileaf collimator (MMLC) was mounted as a field shaping collimator in a proton beamline at the Massachusetts General Hospital. The purpose is to evaluate the device's dosimetric and mechanical properties for the use in a proton beamline. For this evaluation, the authors compared MMLC and brass aperture shaped dose distributions with regard to lateral and depth dose properties. The lateral fall off is generally broader with the MMLC, with difference varying with proton range from 0.2 to 1.2 mm. Central axis depth dose curves did not show a difference in peak-to-entrance ratio, peak width, distal fall off, or range. Two-dimensional dose distributions to investigate the conformity of MMLC shaped doses show that the physical leaf width of approximately 2.5 mm does not have a significant impact. All differences seen in dose distribution shaped by the MMLC versus brass apertures were shown to be clinically insignificant. Measured neutron doses of 0.03-0.13 mSv/Gy for a closed brass beam block (depending on range) are very low compared to the previously published data. Irradiation of the tungsten MMLC, however, produced 1.5-1.8 times more neutrons than brass apertures. Exposure of the staff resulting from activation of the device is below regulatory limits. The measurements established an equivalency between aperture and MMLC shaped dose distributions.

Purpose Microdosimetric measurements were performed at Massachusetts General Hospital, Boston, MA, to assess the dose equivalent external to passively delivered proton fields for various clinical treatment scenarios. Methods and Materials Treatment fields evaluated included a prostate cancer field, cranial and spinal medulloblastoma fields, ocular melanoma field, and a field for an intracranial stereotactic treatment. Measurements were completed with patient-specific configurations of clinically relevant treatment settings using a silicon-on-insulator microdosimeter placed on the surface of and at various depths within a homogeneous Lucite phantom. The dose equivalent and average quality factor were assessed as a function of both lateral displacement from the treatment field edge and distance downstream of the beam's distal edge. Results Dose-equivalent value range was 8.3–0.3 mSv/Gy (2.5–60-cm lateral displacement) for a typical prostate cancer field, 10.8–0.58 mSv/Gy (2.5–40-cm lateral displacement) for the cranial medulloblastoma field, 2.5–0.58 mSv/Gy (5–20-cm lateral displacement) for the spinal medulloblastoma field, and 0.5–0.08 mSv/Gy (2.5–10-cm lateral displacement) for the ocular melanoma field. Measurements of external field dose equivalent for the stereotactic field case showed differences as high as 50% depending on the modality of beam collimation. Average quality factors derived from this work ranged from 2–7, with the value dependent on the position within the phantom in relation to the primary beam. Conclusions This work provides a valuable and clinically relevant comparison of the external field dose equivalents for various passively scattered proton treatment fields.

Purpose Evaluate the rationale for the proposals that prior to a wider use of proton radiation therapy there must be supporting data from phase III clinical trials. That is, would less dose to normal tissues be an advantage to the patient? Methods Assess the basis for the assertion that proton dose distributions are superior to those of photons for most situations. Consider the requirements for determining the risks of normal tissue injury, acute and remote, in the examination of the data from a trial. Analyze the probable cost differential between high technology photon and proton therapy. Evaluate the rationale for phase III clinical trials of proton vs photon radiation therapy when the only difference in dose delivered is a difference in distribution of low LET radiation. Results The distributions of biological effective dose by protons are superior to those by X-rays for most clinical situations, viz. for a defined dose and dose distribution to the target by protons there is a lower dose to non-target tissues. This superiority is due to these physical properties of protons: (1) protons have a finite range and that range is exclusively dependent on the initial energy and the density distribution along the beam path; (2) the Bragg peak; (3) the proton energy distribution may be designed to provide a spread out Bragg peak that yields a uniform dose across the target volume and virtually zero dose deep to the target. Importantly, proton and photon treatment plans can employ beams in the same number and directions (coplanar, non-co-planar), utilize intensity modulation and employ 4D image guided techniques. Thus, the only difference between protons and photons is the distribution of biologically effective dose and this difference can be readily evaluated and quantified. Additionally, this dose distribution advantage should increase the tolerance of certain chemotherapeutic agents and thus permit higher drug doses. The cost of service (not developmental) proton therapy performed in 3–5 gantry centers operating 14–16h/day and 6 days/week is likely to be equal to or less than twice that of high technology X-ray therapy. Conclusions Proton therapy provides superior distributions of low LET radiation dose relative to that by photon therapy for treatment of a large proportion of tumor/normal tissue situations. Our assessment is that there is no medical rationale for clinical trials of protons as they deliver lower biologically effective doses to non-target tissue than do photons for a specified dose and dose distribution to the target. Based on present knowledge, there will be some gain for patients treated by proton beam techniques. This is so even though quantitation of the clinical gain is less secure than the quantitation of reduction in physical dose. Were proton therapy less expensive than X-ray therapy, there would be no interest in conducting phase III trails. The talent, effort and funds required to conduct phase III clinical trials of protons vs photons would surely be more productive in the advancement of radiation oncology if employed to investigate real problems, e.g. the most effective total dose, dose fractionation, definition of CTV and GTV, means for reduction of PTV and the gains and risks of combined modality therapy.

A spread-out Bragg peak (SOBP) is used in proton beam therapy to create a longitudinal conformality of the required dose to the target. In order to create this effect in a passive beam scattering system, a variety of components must operate in conjunction to produce the desired beam parameters. We will describe how the SOBP is generated and will explore the tolerances of the various components and their subsequent effect on the dose distribution. A specific aspect of this investigation includes a case study involving the use of a beam current modulated system. In such a system, the intensity of the beam current can be varied in synchronization with the revolution of the range-modulator wheel. As a result, the weights of the pulled-back Bragg peaks can be individually controlled to produce uniform dose plateaus for a large range of treatment depths using only a small number of modulator wheels.

Proton therapy offers the potential for excellent dose conformity and reduction in integral dose. The superior dose distribution is, however, much more sensitive to changes in radiological depths along the beam path than for photon fields. Respiratory motion can cause such changes for treatments sites like lung, liver, and mediastinum and thus affect the proton dose distribution significantly. We have implemented and commissioned a respiratory-gated system for range-modulated treatment fields. The gating system was designed to ensure that each gate always contains complete modulation cycles so that for any beam segment the delivered dose has the planned depth-dose distribution. Measurements have been made to estimate the time delays for the various components of the system. The total delay between the actual motion and the beam on/off control is in the range of 65-195 ms. Time-resolved dose measurements and film tests were also conducted to examine the overall gating effect.

Intensity modulated proton therapy (IMPT) implies the electromagnetic spatial control of well-circumscribed "pencil beams" of protons of variable energy and intensity. Proton pencil beams take advantage of the charged-particle Bragg peak-the characteristic peak of dose at the end of range-combined with the modulation of pencil beam variables to create target-local modulations in dose that achieves the dose objectives. IMPT improves on X-ray intensity modulated beams (intensity modulated radiotherapy or volumetric modulated arc therapy) with dose modulation along the beam axis as well as lateral, in-field, dose modulation. The clinical practice of IMPT further improves the healthy tissue vs target dose differential in comparison with X-rays and thus allows increased target dose with dose reduction elsewhere. In addition, heavy-charged-particle beams allow for the modulation of biological effects, which is of active interest in combination with dose "painting" within a target. The clinical utilization of IMPT is actively pursued but technical, physical and clinical questions remain. Technical questions pertain to control processes for manipulating pencil beams from the creation of the proton beam to delivery within the patient within the accuracy requirement. Physical questions pertain to the interplay between the proton penetration and variations between planned and actual patient anatomical representation and the intrinsic uncertainty in tissue stopping powers (the measure of energy loss per unit distance). Clinical questions remain concerning the impact and management of the technical and physical questions within the context of the daily treatment delivery, the clinical benefit of IMPT and the biological response differential compared with X-rays against which clinical benefit will be judged. It is expected that IMPT will replace other modes of proton field delivery. Proton radiotherapy, since its first practice 50 years ago, always required the highest level of accuracy and pioneered volumetric treatment planning and imaging at a level of quality now standard in X-ray therapy. IMPT requires not only the highest precision tools but also the highest level of system integration of the services required to deliver high-precision radiotherapy.

We performed a treatment planning study in order to gather basic insight in the effect of setup errors and breathing motion on the cumulative protondose to a lungtumor. We used a simplified geometry that simulates a 50 mm diameter gross tumor volume (GTV) located centrally inside lungtissue. The GTV was expanded with a uniform 5 mm margin into a clinical target volume (CTV) and into a variety of planning target volume (PTV’s). Proton beam apertures were designed to conform the prescribed dose laterally to the PTV while the range compensator was designed to provide distal coverage of the CTV. Different smearing distances were applied to the range compensators, and the cumulative dose in the CTV was evaluated for different combinations of breathing motion and systematic setup errors. Evaluation parameters were the dose to 99% of the CTV ( D 99 ) and the equivalent uniform dose (EUD), with a surviving fraction at 2 Gy of S F 2 = 0.5 . For a single proton field designed to a 15 mm expansion of the CTV and without smearing applied to the range compensator, D 99 of the CTV reduced from 96% for no tumor displacement to 41% and 13% for systematic setup errors of 5 and 10 mm , respectively. For a representative clinical combination, of 5 mm systematic error and 10 mm breathing amplitude, the EUD of the CTV was about 40 Gy (prescribed dose 70 Gy ) regardless the CTV to PTV margin, and without smearing. Smearing the range compensator increases the dose to the CTV substantially with a lateral margin and smearing distance of 7.5 mm providing ample tumor coverage. In this latter case, D 99 of the target volume increased to 87% for a single field treatment plan. Smearing does, however, lead to an increase in dose to normal tissues distal to the clinical target volume. Next to countering geometric mismatches due to patient setup, smearing can also be used to counter the detrimental effects of breathing motion on the dose to the clinical target volume. We show that the lateral margin and smearing distance can be substantially smaller than the maximum tumor displacement due to setup errors and patient breathing, as measured by the D 99 and the EUD.

The magnitude of inter- and intrafractional patient motion has been assessed for a broad set of immobilization devices. Data was analyzed for the three ordinal directions--left-right (x), sup-inf (y), and ant-post (z)--and the combined spatial displacement. We have defined "rigid" and "non-rigid" immobilization devices depending on whether they could be rigidly and reproducibly connected to the treatment couch or not. The mean spatial displacement for intrafractional motion for rigid devices is 1.3 mm compared to 1.9 mm for nonrigid devices. The modified Gill-Thomas-Cosman frame performed best at controlling intrafractional patient motion, with a 95% probability of observing a three-dimensional (3D) vector length of motion (v95) of less than 1.8 mm, but could not be evaluated for interfractional motion. All other rigid and nonrigid immobilization devices had a v95 of more than 3 mm for intrafractional patient motion. Interfractional patient motion was only evaluated for the rigid devices. The mean total interfractional displacement was at least 3.0 mm for these devices while v95 was at least 6.0 mm.

OBJECTIVE: To determine the outcome and toxicity in patients with vestibular schwannomas treated with conventionally fractionated stereotactic radiotherapy (SRT) and to identify prognostic factors that are predictive of outcome. METHODS: Between 1992 and 2001, 70 patients with vestibular schwannomas were treated with linear accelerator-based SRT in our institutions. Eleven patients had neurofibromatosis Type II (NF2). The median age was 53 years (range, 17-82 yrs). The median tumor volume was 2.4 cm 3 (range, 0.05-21.1 cm 3 ). The indications for SRT were distributed as follows: 47% newly diagnosed, 31% progressive tumors after watchful waiting, 3% adjuvant postoperative radiation, and 19% recurrent tumors after surgical resection. The median dose was 54 Gy in 1.8 Gy per fraction, prescribed to 95% of the isodose line. Relocatable stereotactic frames were used for daily treatments. The median follow-up was 45.3 months. RESULTS: Tumor recurrence was defined as progressive enlargement of tumor on follow-up magnetic resonance imaging studies. One patient had a tumor recurrence at 38 months after SRT. The actuarial tumor control rates were 100 and 98% at 3 and 5 years, respectively. Three patients with a median tumor volume of 16.2 cm 3 required surgical resection for persistent or increasing symptoms at a median of 37 months. The actuarial freedom from resection rates were 98 and 92% at 3 and 5 years, respectively. In multivariate analysis, tumor volume at time of treatment was predictive for neurosurgical intervention (surgical resection or shunt placement) after SRT (P = 0.001). The 3- and 5-year actuarial rates of freedom from any neurosurgical intervention were 100 and 97% for patients with tumor volume less than 8 cm 3 and 74 and 47% respectively for patients with tumor of at least 8 cm 3 (P < 0.0001). The 3-year actuarial rates of facial and trigeminal nerve preservation were 99 and 96%, respectively. Surgery before SRT was predictive of posttreatment trigeminal neuropathy. The 3-year actuarial rates of freedom from trigeminal neuropathy were 86 and 98% for patients with and without previous resection, respectively (P = 0.04). There was no difference in tumor control and cranial nerve function preservation rates seen in NF2 patients compared with non-NF2 patients. No second primary cancer or malignant transformation was observed. CONCLUSION: SRT in the conventionally fractionated approach results in a very favorable outcome with minimal toxicity, with results comparable to those of the best of the radiosurgery series. Patients with large tumors are more likely to undergo neurosurgical interventions after SRT. Patients who have undergone previous surgery are at increased risk of developing trigeminal neuropathy.

Purpose To compare treatment plans from standard photon therapy to intensity modulated X-rays (IMRT) and protons for craniospinal axis irradiation and posterior fossa boost in a patient with medulloblastoma. Methods Proton planning was accomplished using an in-house 3D planning system. IMRT plans were developed using the KonRad treatment planning system with 6-MV photons. Results Substantial normal-tissue dose sparing was realized with IMRT and proton treatment of the posterior fossa and spinal column. For example, the dose to 90% of the cochlea was reduced from 101.2% of the prescribed posterior fossa boost dose from conventional X-rays to 33.4% and 2.4% from IMRT and protons, respectively. Dose to 50% of the heart volume was reduced from 72.2% for conventional X-rays to 29.5% for IMRT and 0.5% for protons. Long-term toxicity with emphasis on hearing and endocrine and cardiac function should be substantially improved secondary to nontarget tissue sparing achieved with protons. Conclusion The present study clearly demonstrates the advantage of conformal radiation methods for the treatment of posterior fossa and spinal column in children with medulloblastoma, when compared to conventional X-rays. Of the two conformal treatment methods evaluated, protons were found to be superior to IMRT.

Purpose: To investigate a Greedy Reassignment algorithm in order to mitigate the effects of low weight spots in proton pencil beam scanning (PBS) treatment plans. Methods: To convert a plan from the treatment planning system's (TPS) to a deliverable plan, post processing methods can be used to adjust the spot maps to meets the minimum MU constraint. Existing methods include: deleting low weight spots (Cut method), or rounding spots with weight above/below half the limit up/down to the limit/zero (Round method). An alternative method called Greedy Reassignment was developed in this work in which the lowest weight spot in the field was removed and its weight reassigned equally among its nearest neighbors. The process was repeated with the next lowest weight spot until all spots in the field were above the MU constraint. The algorithm performance was evaluated using plans collected from 190 patients (496 fields) treated at our facility. The evaluation criteria were the γ-index pass rate comparing the pre-processed and post-processed dose distributions. A planning metric was further developed to predict the impact of post-processing on treatment plans for various treatment planning, machine, and dose tolerance parameters. Results: For fields with a gamma pass rate of 90±1%, the metric has a standard deviation equal to 18% of the centroid value. This showed that the metric and γ-index pass rate are correlated for the Greedy Reassignment algorithm. Using a 3rd order polynomial fit to the data, the Greedy Reassignment method had 1.8 times better metric at 90% pass rate compared to other post-processing methods. Conclusion: We showed that the Greedy Reassignment method yields deliverable plans that are closest to the optimized-without-MU-constraint plan from the TPS. The metric developed in this work could help design the minimum MU threshold with the goal of keeping the γ-index pass rate above an acceptable value.

We derive, from first principles, a model to predict the output factors for spread-out Bragg peak proton fields (SOBP). The model is based on the simple observation that the output factor is the ratio of SOBP plateau dose to the dose measured in the ionization reference chamber. The latter, in turn, equates to the entrance dose of the SOBP corrected for inverse square. We use a theoretical derivation of this ratio to establish the relationship between the output factor and the distal range and modulation width of the SOBP. In addition, the theoretical derivation reduces the dependence on the distal range and modulation width into a single factor r = (R - M)/M. We compare the theoretical derivation against measurements obtained at the Northeast Proton Therapy Facility for output factors for clinical fields. The agreement between measurements and prediction is 2.9%.