Dosimetry of a novel focused monoenergetic beam for radiotherapy.

Objective. A novel treatment modality is currently being developed that produces converging monoenergetic x-rays. Conventional application of dosimetric calibration as presented in protocol TG61 is not applicable. Furthermore, the dosimetry of the focal point of the converging beam is on the order of a few millimeters, requiring a high-resolution dosimeter. Here we present a procedure to calibrate radiochromic film for narrow-beam monoenergetic 60 keV photons as well as absolute dosimetry of monoenergetic focused x-rays. A study of the focal spot dose rate after passing through a bone-equivalent material was also done to quantify the effects of heterogeneous materials.Approach.This was accomplished by configuring a polyenergetic beam of equivalent energy using a clinical orthovoltage machine. Calibrated films were then used to perform absolute dosimetry of the converging beam by measuring the beam profile at various depths in water. Main Results.A method for calibrating radiochromic film has been developed and detailed that allows absolute dosimetry of a monoenergetic photon beam. Absolute dosimetry of a focused, mono-energetic beam resulted in a focal spot dose rate of ∼30 cGy min-1at a depth of 5 cm in water.Significance.This work serves to establish a dosimetry protocol for mono-energetic beam absolute dosimetry as well as the use of such a method for measurement of a novel teletherapy modality.

Analysis of a novel X-ray lens for converging beam radiotherapy.

We describe the development and analysis of a new teletherapy modality that, through a novel approach to targeted radiation delivery, has the potential to provide greater conformality than conventional photon-based treatments. The proposed system uses an X-ray lens to reflect photons from a conventional X-ray tube toward a focal spot. The resulting dose distributions have a highly localized peak dose, with lower doses in the converging radiation cone. Physical principles governing the design of this system are presented, along with a series of measurements analyzing various characteristics of the converging beam. The beam was designed to be nearly monoenergetic (~ 59 keV), with an energy bandwidth of approximately 10 keV allowing for treatment energies lower than conventional therapies. The focal spot was measured to be approximately 2.5 cm long and 4 mm wide. Mounting the proposed X-ray delivery system on a robotic arm would allow sub-millimeter accuracy in focal spot positioning, resulting in highly conformal dose distribution via the optimal placement of individual focal spots within the target volume. Aspects of this novel radiation beam are discussed considering their possible clinical application as a treatment approach that takes maximum advantage of the unique properties afforded by converging X-ray beam therapy.

Mixed Effect Modeling of Dose and Linear Energy Transfer Correlations With Brain Image Changes After Intensity Modulated Proton Therapy for Skull Base Head and Neck Cancer.

PURPOSE: Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT. METHODS AND MATERIALS: For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LETd) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve. RESULTS: An overall statistically significant RAIC association with dose and LETd was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30-2.72) for dose and 2.68 (1.93-4.93) for LETd, respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LETd effect demonstrated increased risk of RAIC with increasing LETd for the majority of patients. Estimated probability of RAIC with LETd = 1 keV/µm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD15 were estimated to be 63.6 and 50.1 Gy with LETd equal to 2 and 5 keV/µm, respectively. CONCLUSIONS: Our results suggest that the LETd effect could be of clinical significance for some patients; LETd assessment in clinical treatment plans should therefore be taken into consideration.

A framework for voxel-based assessment of biological effect after proton radiotherapy in pediatric brain cancer patients using multi-modal imaging.

INTRODUCTION: The exact dependence of biological effect on dose and linear energy transfer (LET) in human tissue when delivering proton therapy is unknown. In this study, we propose a framework for measuring this dependency using multi-modal image-based assays with deformable registrations within imaging sessions and across time. MATERIALS AND METHODS: 3T MRI scans were prospectively collected from 6 pediatric brain cancer patients before they underwent proton therapy treatment, and every 3 months for a year after treatment. Scans included T1-weighted with contrast enhancement (T1), T2-FLAIR (T2) and fractional anisotropy (FA) images. In addition, the planning CT, dose distributions and Monte Carlo-calculated LET distributions were collected. A multi-modal deformable image registration framework was used to create a dataset of dose, LET and imaging intensities at baseline and follow-up on a voxel-by-voxel basis. We modelled the biological effect of dose and LET from proton therapy using imaging changes over time as a surrogate for biological effect. We investigated various models to show the feasibility of the framework to model imaging changes. To account for interpatient and intrapatient variations, we used a nested generalized linear mixed regression model. The models were applied to predict imaging changes over time as a function of dose and LET for each modality. RESULTS: Using the nested models to predict imaging changes, we saw a decrease in the FA signal as a function of dose; however, the signal increased with increasing LET. Similarly, we saw an increase in T2 signal as a function of dose, but a decrease in signal with LET. We saw no changes in T1 voxel values as a function of either dose or LET. CONCLUSIONS: The imaging changes could successfully model biological effect as a function of dose and LET using our proposed framework. Due to the low number of patients, the imaging changes observed for FA and T2 scans were not marked enough to draw any firm conclusions.

Devices for dosimetric measurements and quality assurance of the Xstrahl 300 orthovoltage unit.

The Xstrahl 300 orthovoltage unit is designed to deliver kilovoltage radiation therapy using the appositional technique. However, it is not equipped with some typical linear accelerator features, such as mechanical distance indicator and crosshair projection, which are useful for facilitating equipment setup during various quality assurance (QA) and research activities. Therefore, we designed and constructed slip-in devices to facilitate QA for dosimetric measurements of our Xstrahl 300 unit. These include: (a) an ion chamber positioning system for dosimetric measurements, (b) a mechanical pointer for setting dosimeter distance to a nominal 50 cm, and (c) a crosshair projector with built-in light to facilitate alignment of dosimeter to the center of the radiation field. These devices provide a high degree of setup reproducibility thereby minimizing setup errors. We used these devices to perform QA of the Xstrahl 300 orthovoltage unit. One of the QA tests we perform is a constancy check of beam output and energy. Our data since start of clinical use of this unit (approximately 2.5 yr) show dose outputs to be remarkably reproducible (2σ = ±0.4%) for all three clinical beams (75, 125, and 250 kVp). These devices have provided both convenience and high-precision during the unit's commissioning, and continue to provide the same for various QA activities on the Xstrahl 300 orthovoltage unit.

Decreased heart dose with deep inspiration breath hold for the treatment of gastric lymphoma with IMRT.

We hypothesized that deep inspiration breath-hold (DIBH) and computed-tomography image-guided radiotherapy (CT-IGRT) may be beneficial to decrease dose to organs at risk (OARs), when treating the stomach with radiotherapy for lymphoma. We compared dosimetric parameters of OARs from plans generated using free-breathing (FB) versus DIBH for 10 patients with non-Hodgkin lymphoma involving the stomach treated with involved site radiotherapy. All patients had 4DCT and DIBH scans. Planning was performed with intensity modulated radiotherapy (IMRT) to 30.6 Gy in 17 fractions. Differences in target volume and dosimetric parameters were assessed using a paired two-sided t-test. All heart and left ventricle parameters including mean dose, V30, V20, V10, and V5 were statistically significantly lower with DIBH. For IMRT-FB plans the average mean heart dose was 4.9 Gy compared to 2.6 Gy for the IMRT-DIBH group (p < 0.001). There was a statistically significant decrease in right kidney dose with DIBH. For lymphoma patients treated to the stomach with IMRT, DIBH provides superior OAR sparing compared to FB-based planning, most notably reducing dose to the heart and left ventricle. This strategy could be considered when treating other gastric malignancies.

Radiation-Induced Hypothyroidism After Radical Intensity Modulated Radiation Therapy for Oropharyngeal Carcinoma.

PURPOSE: To evaluate 2 published normal tissue complication probability models for radiation-induced hypothyroidism (RHT) on a large cohort of oropharyngeal carcinoma (OPC) patients who were treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: OPC patients treated with retrievable IMRT Digital Imaging and Communications in Medicine (DICOMs) data and available baseline and follow-up thyroid function tests were included. Mean dose (Dmean) to the thyroid gland (TG) and its volume were calculated. The study outcome was clinical HT at least 6 months after radiation therapy, which was defined as grade ≥2 HT per Common Terminology Criteria for Adverse Events grading system (symptomatic hypothyroidism that required thyroid replacement therapy). Regression analyses and Wilcoxon rank-sum test were used. Receiver operating characteristic curves and area under the curve for the fitted model were calculated. RESULTS: In the study, 360 OPC patients were included. The median age was 58 years. Most tumors (51%) originated from the base of tongue. IMRT-split field was used in 95%, and median radiation therapy dose was 69.96 Gy. In the study, 233 patients (65%) developed clinical RHT that required thyroid replacement therapy. On multivariate analysis higher Dmean and smaller TG volume maintained the statistically significant association with the risk of clinical RHT (P < .0001). Dmean was significantly higher in patients with clinical RHT versus those without (50 vs 42 Gy, P < .0001). Patients with RHT had smaller TG volume compared with those without (11.8 compared with 12.8 mL, P < .0001). AUC of 0.72 and 0.66 were identified for fitted model versus for the applied Boomsma et al and Cella et al models, respectively. CONCLUSIONS: Volume and Dmean of the TG are important predictors of clinical RHT and shall be integrated into normal tissue complication probability models for RHT. Dmean and thyroid volume should be considered during the IMRT plan optimization in OPC patients.

A DNA damage multiscale model for NTCP in proton and hadron therapy.

PURPOSE: To develop a first principle and multiscale model for normal tissue complication probability (NTCP) as a function of dose and LET for proton and in general for particle therapy with a goal of incorporating nanoscale radio-chemical to macroscale cell biological pathways, spanning from initial DNA damage to tissue late effects. METHODS: The method is a combination of analytical and multiscale computational steps including (a) derivation of functional dependencies of NTCP on DNA-driven cell lethality in nanometer and mapping to dose and LET in millimeter, and (b) three-dimensional-surface fitting to Monte Carlo data set generated based on postradiation image change and gathered for a cohort of 14 pediatric patients treated by scanning beam of protons for ependymoma. We categorize voxel-based dose and LET associated with development of necrosis in NTCP. RESULT: Our model fits well the clinical data, generated for postradiation tissue toxicity and necrosis. The fitting procedure results in extraction of in vivo radio-biological α-ß indices and their numerical values. DISCUSSION AND CONCLUSION: The NTCP model, explored in this work, allows to correlate the tissue toxicities to DNA initial damage, cell lethality and the properties and qualities of radiation, dose, and LET.

Fixed- versus Variable-RBE Computations for Intensity Modulated Proton Therapy.

PURPOSE: To evaluate how using models of proton therapy that incorporate variable relative biological effectiveness (RBE) versus the current practice of using a fixed RBE of 1.1 affects dosimetric indices on treatment plans for large cohorts of patients treated with intensity modulated proton therapy (IMPT). METHODS AND MATERIALS: Treatment plans for 4 groups of patients who received IMPT for brain, head-and-neck, thoracic, or prostate cancer were selected. Dose distributions were recalculated in 4 ways: 1 with a fast-dose Monte Carlo calculator with fixed RBE and 3 with RBE calculated to 3 different models-McNamara, Wedenberg, and repair-misrepair-fixation. Differences among dosimetric indices (D02, D50, D98, and mean dose) for target volumes and organs at risk (OARs) on each plan were compared between the fixed-RBE and variable-RBE calculations. RESULTS: In analyses of all target volumes, for which the main concern is underprediction or RBE less than 1.1, none of the models predicted an RBE less than 1.05 for any of the cohorts. For OARs, the 2 models based on linear energy transfer, McNamara and Wedenberg, systematically predicted RBE >1.1 for most structures. For the mean dose of 25% of the plans for 2 OARs, they predict RBE equal to or larger than 1.4, 1.3, 1.3, and 1.2 for brain, head-and-neck, thorax, and prostate, respectively. Systematically lower increases in RBE are predicted by repair-misrepair-fixation, with a few cases (eg, femur) in which the RBE is less than 1.1 for all plans. CONCLUSIONS: The variable-RBE models predict increased doses to various OARs, suggesting that strategies to reduce high-dose linear energy transfer in critical structures should be developed to minimize possible toxicity associated with IMPT.

Patterns of Local-Regional Failure After Intensity Modulated Radiation Therapy or Passive Scattering Proton Therapy With Concurrent Chemotherapy for Non-Small Cell Lung Cancer.

PURPOSE: We compared differences in patterns of locoregional failure, and the influence of adaptive planning on those patterns, in patients who received passive scattering proton therapy (PSPT) versus intensity modulated photon therapy (IMRT) for non-small cell lung cancer. METHODS AND MATERIALS: Treatment simulation computed tomography scans and dose distributions were registered with images depicting the recurrence. Local failure (LF) was defined as failure within the internal target volume (ITV); marginal failure (MF) as failure between the ITV and planning target volume (PTV) plus a 10-mm margin (PTV+10mm); and regional failure (RF) as outside the PTV+10mm. Weekly during-treatment 4-dimensional computed tomography simulation and verification plans were obtained for all patients. Adaptive plans were developed if the verification plan showed deviations in protocol-specified dose distribution, and failure locations were recorded for those patients as well. RESULTS: Of the 212 patients analyzed, most (152 [72%]) had no failure; of the 60 patients with failure, 27 (45%) had LF (within the ITV), 23 (38%) had MF (between the ITV and PTV+10mm), and 10 (17%) had RF (>10 mm outside the PTV). MF rates were no different for IMRT patients (16 of 136 [12%]) or PSPT patients (7 of 76 [9%], log-rank P = .558). The only independent predictor of MF on Cox proportional hazards analysis was T3-4 status. Large tumors and use of PSPT independently predicted the need for adaptive planning. Although 5-year overall survival rates were poorer for patients with large tumors versus small tumors (P < .001), the rates were similar for patients with large tumors who received adaptive planning versus small tumors. CONCLUSIONS: No differences in LF, MF, or RF patterns were found for IMRT versus PSPT. Proton therapy more often required adaptive planning, and the techniques used for adaptive planning did not compromise tumor control. Response to chemoradiation by larger tumors predicted favorable survival.

Hitting a Moving Target: Successful Management of Diffuse Large B-cell Lymphoma Involving the Mesentery With Volumetric Image-guided Intensity Modulated Radiation Therapy.

INTRODUCTION: We report successful treatment of mesenteric diffuse large B-cell lymphoma (DLBCL) using localized involved site radiation therapy (ISRT), intensity modulated radiation therapy (IMRT), and daily computed tomography (CT)-image guidance. PATIENTS AND METHODS: Patients with mesenteric DLBCL treated with RT between 2011 and 2017 were reviewed. Clinical and treatment characteristics were analyzed for an association with local control, progression-free survival (PFS), and overall survival. RESULTS: Twenty-three patients were eligible. At diagnosis, the median age was 52 years (range, 38-76 years), and 57% (n = 13) had stage I/II DLBCL. All patients received frontline chemotherapy (ChT) (R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone], n = 19; dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin], n = 4) with median 6 cycles. Prior to RT, salvage ChT for refractory DLBCL was given to 43% (n = 10) and autologous stem cell transplantation was administered in 13% (n = 3). At the time of RT, positron emission tomography-CT revealed 5-point scale of 1 to 3 (48%; n = 11), 4 (9%; n = 2), and 5 (44%; n = 10). All patients received IMRT, daily CT imaging, and ISRT. The median RT dose was 40 Gy (range, 16.2-49.4 Gy). Relapse or progression occurred in 22% (n = 5). At a median follow-up of 37 months, the 3-year local control, PFS, and overall survival rates were 80%, 75%, and 96%, respectively. Among patients treated with RT after complete metabolic response to frontline ChT (n = 8), the 3-year PFS was 100%, compared with 61% for patients with a history of chemorefractory DLBCL (n = 15; P = .055). Four of the 5 relapses occurred in patients with 5-point scale of 5 prior to RT (P = .127). CONCLUSION: Mesenteric involvement of DLBCL can be successfully targeted with localized ISRT fields using IMRT and daily CT-image guidance.

Low- and middle-income countries can reduce risks of subsequent neoplasms by referring pediatric craniospinal cases to centralized proton treatment centers.

Few children with cancer in low- and middle-income countries (LMICs) have access to proton therapy. Evidence exists to support replacing photon therapy with proton therapy to reduce the incidence of secondary malignant neoplasms (SMNs) in childhood cancer survivors. The purpose of this study was to estimate the potential reduction in SMN incidence and in SMN mortality for pediatric medulloblastoma patients in LMICs if proton therapy were made available to them. For nine children of ages 2 to 14 years, we calculated the equivalent dose in organs or tissues at risk for radiogenic SMNs from therapeutic and stray radiation for photon craniospinal irradiation (CSI) in a LMIC and proton CSI in a high-income country. We projected the lifetime risks of SMN incidence and SMN mortality for every SMN site with a widely-used model from the literature. We found that the average total lifetime attributable risks of incidence and mortality were very high for both photon CSI (168% and 41%, respectively) and proton CSI (88% and 26%, respectively). SMNs having the highest risk of mortality were lung cancer (16%), non-site-specific solid tumors (16%), colon cancer (5.9%), leukemia (5.4%), and for girls breast cancer (5.0%) after photon CSI and non-site-specific solid tumors (12%), lung cancer (11%), and leukemia (4.8%) after proton CSI. The risks were higher for younger children than for older children and higher for girls than for boys. The ratios of proton CSI to photon CSI of total risks of SMN incidence and mortality were 0.56 (95% CI, 0.37 to 0.75) and 0.64 (95% CI, 0.45 to 0.82), respectively, averaged over this sample group. In conclusion, proton therapy has the potential to lessen markedly subsequent SMNs and SMN fatalities in survivors of childhood medulloblastoma in LMICs, for example, through regional centralized care. Additional methods should be explored urgently to reduce therapeutic-field doses in organs and tissues at risk for SMN, especially in the lungs, colon, and breast tissues.

National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury.

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.

Comparison of Monte Carlo and analytical dose computations for intensity modulated proton therapy.

To evaluate the effect of approximations in clinical analytical calculations performed by a treatment planning system (TPS) on dosimetric indices in intensity modulated proton therapy. TPS calculated dose distributions were compared with dose distributions as estimated by Monte Carlo (MC) simulations, calculated with the fast dose calculator (FDC) a system previously benchmarked to full MC. This study analyzed a total of 525 patients for four treatment sites (brain, head-and-neck, thorax and prostate). Dosimetric indices (D02, D05, D20, D50, D95, D98, EUD and Mean Dose) and a gamma-index analysis were utilized to evaluate the differences. The gamma-index passing rates for a 3%/3 mm criterion for voxels with a dose larger than 10% of the maximum dose had a median larger than 98% for all sites. The median difference for all dosimetric indices for target volumes was less than 2% for all cases. However, differences for target volumes as large as 10% were found for 2% of the thoracic patients. For organs at risk (OARs), the median absolute dose difference was smaller than 2 Gy for all indices and cohorts. However, absolute dose differences as large as 10 Gy were found for some small volume organs in brain and head-and-neck patients. This analysis concludes that for a fraction of the patients studied, TPS may overestimate the dose in the target by as much as 10%, while for some OARs the dose could be underestimated by as much as 10 Gy. Monte Carlo dose calculations may be needed to ensure more accurate dose computations to improve target coverage and sparing of OARs in proton therapy.

Differences in Normal Tissue Response in the Esophagus Between Proton and Photon Radiation Therapy for Non-Small Cell Lung Cancer Using In Vivo Imaging Biomarkers.

PURPOSE: To determine whether there exists any significant difference in normal tissue toxicity between intensity modulated radiation therapy (IMRT) or proton therapy for the treatment of non-small cell lung cancer. METHODS AND MATERIALS: A total of 134 study patients (n=49 treated with proton therapy, n=85 with IMRT) treated in a randomized trial had a previously validated esophageal toxicity imaging biomarker, esophageal expansion, quantified during radiation therapy, as well as esophagitis grade (Common Terminology Criteria for Adverse Events version 3.0), on a weekly basis during treatment. Differences between the 2 modalities were statically analyzed using the imaging biomarker metric value (Kruskal-Wallis analysis of variance), as well as the incidence and severity of esophagitis grade (χ2 and Fisher exact tests, respectively). The dose-response of the imaging biomarker was also compared between modalities using esophageal equivalent uniform dose, as well as delivered dose to an isotropic esophageal subvolume. RESULTS: No statistically significant difference in the distribution of esophagitis grade, the incidence of grade ≥3 esophagitis (15 and 11 patients treated with IMRT and proton therapy, respectively), or the esophageal expansion imaging biomarker between cohorts (P>.05) was found. The distribution of imaging biomarker metric values had similar distributions between treatment arms, despite a slightly higher dose volume in the proton arm (P>.05). Imaging biomarker dose-response was similar between modalities for dose quantified as esophageal equivalent uniform dose and delivered esophageal subvolume dose. Regardless of treatment modality, there was high variability in imaging biomarker response, as well as esophagitis grade, for similar esophageal doses between patients. CONCLUSIONS: There was no significant difference in esophageal toxicity from either proton- or photon-based radiation therapy as quantified by esophagitis grade or the esophageal expansion imaging biomarker.

Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma.

BACKGROUND AND PURPOSE: A constant relative biological effectiveness (RBE) is used for clinical proton therapy; however, experimental evidence indicates that RBE can vary. We analyzed pediatric ependymoma patients who received proton therapy to determine if areas of normal tissue damage indicated by post-treatment image changes were associated with increased biological dose effectiveness. MATERIAL AND METHODS: Fourteen of 34 children showed T2-FLAIR hyperintensity on post-treatment magnetic resonance (MR) images. We delineated regions of treatment-related change and calculated dose and linear energy transfer (LET) distributions with Monte Carlo. Voxel-level image change data were fit to a generalized linear model incorporating dose and LET. Cross-validation was used to determine model parameters and for receiver operating characteristic curve analysis. Tolerance dose (TD50; dose at which 50% of patients would experience toxicity) was interpolated from the model. RESULTS: Image changes showed dependence on increasing LET and dose. TD50 decreased with increasing LET, indicating an increase in biological dose effectiveness. The cross-validated area under the curve for the model was 0.91 (95% confidence interval 0.88-0.94). CONCLUSIONS: Our correlation of changes on MR images after proton therapy with increased LET constitutes the first clinical evidence of variable proton biological effectiveness.

Approaches to reducing photon dose calculation errors near metal implants.

PURPOSE: Dose calculation errors near metal implants are caused by limitations of the dose calculation algorithm in modeling tissue/metal interface effects as well as density assignment errors caused by imaging artifacts. The purpose of this study was to investigate two strategies for reducing dose calculation errors near metal implants: implementation of metal-based energy deposition kernels in the convolution/superposition (C/S) dose calculation method and use of metal artifact reduction methods for computed tomography (CT) imaging. METHODS: Both error reduction strategies were investigated using a simple geometric slab phantom with a rectangular metal insert (composed of titanium or Cerrobend), as well as two anthropomorphic phantoms (one with spinal hardware and one with dental fillings), designed to mimic relevant clinical scenarios. To assess the dosimetric impact of metal kernels, the authors implemented titanium and silver kernels in a commercial collapsed cone C/S algorithm. To assess the impact of CT metal artifact reduction methods, the authors performed dose calculations using baseline imaging techniques (uncorrected 120 kVp imaging) and three commercial metal artifact reduction methods: Philips Healthcare's o-mar, GE Healthcare's monochromatic gemstone spectral imaging (gsi) using dual-energy CT, and gsi with metal artifact reduction software (mars) applied. For the simple geometric phantom, radiochromic film was used to measure dose upstream and downstream of metal inserts. For the anthropomorphic phantoms, ion chambers and radiochromic film were used to quantify the benefit of the error reduction strategies. RESULTS: Metal kernels did not universally improve accuracy but rather resulted in better accuracy upstream of metal implants and decreased accuracy directly downstream. For the clinical cases (spinal hardware and dental fillings), metal kernels had very little impact on the dose calculation accuracy (<1.0%). Of the commercial CT artifact reduction methods investigated, the authors found that o-mar was the most consistent method, resulting in either improved dose calculation accuracy (dental case) or little impact on calculation accuracy (spine case). gsi was unsuccessful at reducing the severe artifacts caused by dental fillings and had very little impact on calculation accuracy. gsi with mars on the other hand gave mixed results, sometimes introducing metal distortion and increasing calculation errors (titanium rectangular implant and titanium spinal hardware) but other times very successfully reducing artifacts (Cerrobend rectangular implant and dental fillings). CONCLUSIONS: Though successful at improving dose calculation accuracy upstream of metal implants, metal kernels were not found to substantially improve accuracy for clinical cases. Of the commercial artifact reduction methods investigated, o-mar was found to be the most consistent candidate for all-purpose CT simulation imaging. The mars algorithm for gsi should be used with caution for titanium implants, larger implants, and implants located near heterogeneities as it can distort the size and shape of implants and increase calculation errors.