LETd Optimization Verification With an SOI Microdosimeter.

PURPOSE: A first of its kind experimental verification of dose-averaged linear energy transfer (LETd) optimized treatment plans for proton therapy has been carried out using a silicon-on-insulator microdosimeter at the Massachusetts General Hospital (MGH), Boston, USA. METHODS AND MATERIALS: Three clinical treatment plans of a typical ependymoma structure set were designed using the standard clinical approach, the proposed protocol approach, and a one-field approach. The plans were then reoptimized to reduce the LETd-weighted dose in the brain stem. All six plans were delivered in a solid water phantom and the experimental yD‾ measured. RESULTS: After LETd optimization, a reduction in yD‾ was found within the brain stem by an average of 12%, 19%, and 4% for the clinical, protocol, and one-field plans, respectively, while maintaining adequate coverage of the tumor structure. The experimental LETd-weighted doses were in agreement with the treatment planning system calculations and Monte Carlo simulations and reinforced the improvement of the optimization. CONCLUSIONS: This work demonstrates the first experimental verification of the clinical implementation of LETd optimization for patient treatment with proton therapy.

Monte Carlo study of out-of-field exposure in carbon-ion radiotherapy: Organ doses in pediatric brain tumor treatment.

PURPOSE: To estimate out-of-field doses during carbon-ion radiotherapy (CIRT) for pediatric cerebellar ependymoma. METHODS: Given that the out-of-field dose of CIRT depends on beam parameters, we set them for treatment of typical pediatric cerebellar ependymoma based on a previous study. The out-of-field dose during CIRT for pediatric cerebellar ependymoma was then estimated using the Particle and Heavy-Ion Transport code System with Monte Carlo simulations and a computational phantom developed at the University of Florida. From the simulation results, out-of-field doses at dose equivalents of passive beam and active scanning beam CIRT were calculated and compared to the secondary neutron-equivalent dose of passive beam CIRT and proton therapy. RESULTS: The out-of-field dose equivalent decreases from 1.45 mSv/Gy (relative biological effectiveness - RBE) at the thyroid to 0.06 mSv/Gy (RBE) at the bladder, verifying decay as the distance from the treatment target increases. The out-of-field neutron-equivalent dose in organs per prescribed dose for passive beam CIRT is lower than that for passive beam proton therapy. Moreover, the out-of-field organ dose equivalent per prescribed dose for the active scanning beam CIRT is lower than that for the passive beam CIRT. CONCLUSIONS: Active scanning beam CIRT is promising for pediatric cerebellar ependymoma regarding out-of-field exposure, outperforming the comparison radiotherapy modalities.

Can differences in linear energy transfer and thus relative biological effectiveness compromise the dosimetric advantage of intensity-modulated proton therapy as compared to passively scattered proton therapy?

PURPOSE: To investigate the effect of differences in linear energy transfer (LET) and thus the relative biological effectiveness (RBE) between passively scattered proton therapy (PS) and pencil-beam scanning intensity-modulated proton therapy (IMPT). METHODS: IMPT treatment plans were generated for six ependymoma patients, originally treated with PS, using the original plan's computed tomography image sets and beam directions, and its dose-volume values as optimization constraints. Two beam spot sizes and both single-field optimization (SFO) and multi-field optimization (MFO) techniques were used for each patient. Three-dimensional variable-RBE-weighted dose distributions were computed, using Monte Carlo calculated dose and LET distributions, and a linear dose and LET-based RBE model, and were compared between the two delivery methods. RESULTS: Increased target dose coverage and decreased mean and maximum dose to the OARs was achieved with IMPT compared to PS, for constant RBE value of 1.1. Nevertheless, the maximum variable-RBE-weighted dose to the brainstem, was increased up to 6% for the IMPT plans compared to the corresponding PS plans. CONCLUSIONS: IMPT can be dosimetrically superior to PS for ependymoma patients. However, caution should be exercised so that the increased dose conformity is not counteracted by an increase in radiobiological effect in adjacent critical structures.

Socioeconomic factors affect the selection of proton radiation therapy for children.

BACKGROUND: Proton radiotherapy remains a limited resource despite its clear potential for reducing radiation doses to normal tissues and late effects in children in comparison with photon therapy. This study examined the impact of race and socioeconomic factors on the use of proton therapy in children with solid malignancies. METHODS: This study evaluated 12,101 children (age ≤ 21 years) in the National Cancer Data Base who had been diagnosed with a solid malignancy between 2004 and 2013 and had received photon- or proton-based radiotherapy. Logistic regression analysis was used to evaluate patient, tumor, and socioeconomic variables affecting treatment with proton radiotherapy versus photon radiotherapy. RESULTS: Eight percent of the patients in the entire cohort received proton radiotherapy, and this proportion increased between 2004 (1.7%) and 2013 (17.5%). Proton therapy was more frequently used in younger patients (age ≤ 10 years; odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.2) and in patients with bone/joint primaries and ependymoma, medulloblastoma, and rhabdomyosarcoma histologies (P < .05). Patients with metastatic disease were less likely to receive proton therapy (OR, 0.4; 95% CI, 0.3-0.6). Patients with private/managed care were more likely than patients with Medicaid or no insurance to receive proton therapy (P < .0001). A higher median household income and educational attainment were also associated with increased proton use (P < .001). Patients treated with proton therapy versus photon therapy were more likely to travel more than 200 miles (13% vs 5%; P < .0001). CONCLUSIONS: Socioeconomic factors affect the use of proton radiotherapy in children. Whether this disparity is related to differences in the referral patterns, the knowledge of treatment modalities, or the ability to travel for therapy needs to be further clarified. Improving access to proton therapy in underserved pediatric populations is essential. Cancer 2017;123:4048-56. © 2017 American Cancer Society.

Proton Treatment Techniques for Posterior Fossa Tumors: Consequences for Linear Energy Transfer and Dose-Volume Parameters for the Brainstem and Organs at Risk.

PURPOSE: In proton therapy of posterior fossa tumors, at least partial inclusion of the brainstem in the target is necessary because of its proximity to the tumor and required margins. Additionally, the preferred beam geometry results in directing the field distal edge toward this critical structure, raising concerns for brainstem toxicity. Some treatment techniques place the beam's distal edge within the brainstem (dose-sparing techniques), and others avoid elevated linear energy transfer (LET) of the proton field by placing the distal edge beyond it (LET-sparing techniques). Hybrid approaches are also being used. We examine the dosimetric efficacy of these techniques, accounting for LET-dependent and dose-dependent variable relative biologic effectiveness (RBE) distributions. METHODS: Six techniques were applied in ependymoma cases: (a) 3-field dose-sparing; (b) 3-field LET-sparing; (c) 2-field dose-sparing, wide angles; (d) 2-field LET-sparing, wide angles; (e) 2-field LET-sparing, steep angles; and (f) 2-field LET-sparing with feathered distal end. Monte Carlo calculated dose, LET, and RBE-weighted dose distributions were compared. RESULTS: Decreased LET values in the brainstem by LET-sparing techniques were accompanied by higher, not statistically significant, median dose: 53.6 Gy(RBE), 53.4 Gy(RBE), and 54.3 Gy(RBE) for techniques (b), (d), and (e) versus 52.1 Gy(RBE) for technique (a). Accounting for variable RBE distributions, the brainstem volume receiving at least 55 Gy(RBE) increased from 72.5% for technique (a) to 80.3% for (b) (P<.01) and from 70.7% for technique (c) to 77.6% for (d) (P<.01). Less than 2%, but statistically significant, decrease in maximum variable RBE-weighted brainstem dose was observed for the LET-sparing techniques compared with the corresponding dose-sparing (P=.03 and .004). CONCLUSIONS: Extending the proton range beyond the brainstem to reduce LET results in clinically comparable maximum radiobiologic effective dose to this sensitive structure. However this method significantly increasing the brainstem volume receiving RBE-weighted dose higher than 55 Gy(RBE) with possible consequences based on known dose-volume parameters for increased toxicity.

Reoptimization of Intensity Modulated Proton Therapy Plans Based on Linear Energy Transfer.

PURPOSE: We describe a treatment plan optimization method for intensity modulated proton therapy (IMPT) that avoids high values of linear energy transfer (LET) in critical structures located within or near the target volume while limiting degradation of the best possible physical dose distribution. METHODS AND MATERIALS: To allow fast optimization based on dose and LET, a GPU-based Monte Carlo code was extended to provide dose-averaged LET in addition to dose for all pencil beams. After optimizing an initial IMPT plan based on physical dose, a prioritized optimization scheme is used to modify the LET distribution while constraining the physical dose objectives to values close to the initial plan. The LET optimization step is performed based on objective functions evaluated for the product of LET and physical dose (LET×D). To first approximation, LET×D represents a measure of the additional biological dose that is caused by high LET. RESULTS: The method is effective for treatments where serial critical structures with maximum dose constraints are located within or near the target. We report on 5 patients with intracranial tumors (high-grade meningiomas, base-of-skull chordomas, ependymomas) in whom the target volume overlaps with the brainstem and optic structures. In all cases, high LET×D in critical structures could be avoided while minimally compromising physical dose planning objectives. CONCLUSION: LET-based reoptimization of IMPT plans represents a pragmatic approach to bridge the gap between purely physical dose-based and relative biological effectiveness (RBE)-based planning. The method makes IMPT treatments safer by mitigating a potentially increased risk of side effects resulting from elevated RBE of proton beams near the end of range.

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.

The use of proton therapy in the treatment of benign or low-grade pediatric brain tumors.

Radiation therapy (RT) plays a critical role in the local tumor control of benign and low-grade central nervous system tumors in children but is not without the risk of long-term treatment-related sequelae. Proton therapy (PRT) is an advanced RT modality with a unique dose-deposition pattern that allows for treatment of a target volume with reduced scatter dose delivered to normal tissues compared with conventional photon RT and is now increasingly utilized in children with the hope of mitigating radiation-induced late effects. This article reviews the current literature evaluating the use of PRT in benign and low-grade pediatric central nervous system tumors such as low-grade glioma, craniopharyngioma, and ependymoma. Multiple dosimetric studies support the use of PRT by demonstrating the ability of PRT to better spare critical structures important for cognitive development, endocrine function, and hearing preservation and to reduce the total body dose associated with second malignancy risk. Early clinical data demonstrate that PRT is well tolerated with rates of local tumor control comparable to conventional photon RT series, and long-term clinical data are awaited.

Proton therapy dose distribution comparison between Monte Carlo and a treatment planning system for pediatric patients with ependymoma.

PURPOSE: Compare dose distributions for pediatric patients with ependymoma calculated using a Monte Carlo (MC) system and a clinical treatment planning system (TPS). METHODS: Plans from ten pediatric patients with ependymoma treated using double scatter proton therapy were exported from the TPS and calculated in our MC system. A field by field comparison of the distal edge (80% and 20%), distal fall off (80% to 20%), field width (50% to 50%), and penumbra (80% to 20%) were examined. In addition, the target dose for the full plan was compared. RESULTS: For the 32 fields from the 10 patients, the average differences of distal edge at 80% and 20% on central axis between MC and TPS are -1.9 ± 1.7 mm (p < 0.001) and -0.6 ± 2.3 mm (p = 0.13), respectively. Excluding the fields that ranged out in bone or an air cavity, the 80% difference was -0.9 ± 1.7 mm (p = 0.09). The negative value indicates that MC was on average shallower than TPS. The average difference of the 63 field widths of the 10 patients is -0.7 ± 1.0 mm (p < 0.001), negative indicating on average the MC had a smaller field width. On average, the difference in the penumbra was 2.3 ± 2.1 mm (p < 0.001). The average of the mean clinical target volume dose differences is -1.8% (p = 0.001), negative indicating a lower dose for MC. CONCLUSIONS: Overall, the MC system and TPS gave similar results for field width, the 20% distal edge, and the target coverage. For the 80% distal edge and lateral penumbra, there was slight disagreement; however, the difference was less than 2 mm and occurred primarily in highly heterogeneous areas. These differences highlight that the TPS dose calculation cannot be automatically regarded as correct.

Kilovoltage imaging doses in the radiotherapy of pediatric cancer patients.

PURPOSE: To investigate doses induced by kilovoltage cone-beam computed tomography (kVCBCT) to pediatric cancer patients undergoing radiotherapy, as well as strategies for dose reduction. METHODS AND MATERIALS: An EGS4 Monte Carlo code was used to calculate three-dimensional dose deposition due to kVCBCT on 4 pediatric cancer patients. Absorbed doses to various organs were analyzed for both half-fan and full-fan modes. Clinical conditions, such as distance from organ at risk (OAR) to CBCT field border, kV peak energy, and testicular shielding, were studied. RESULTS: The mean doses induced by one CBCT scan operated at 125 kV in half-fan mode to testes, liver, kidneys, femoral heads, spinal cord, brain, eyes, lens, and optical nerves were 2.9, 4.7, 7.7, 10.5, 8.8, 7.6, 7.7, 7.8, and 7.2 cGy, respectively. Increasing the distances from OARs to CBCT field border greatly reduced the doses to OARs, ranging from 33% reduction for spinal cord to 2300% reduction for testes. As photon beam energy increased from 60 to 125 kV, the dose increase due to kVCBCT ranged from 170% for lens to 460% for brain and spinal cord. A testicular shielding made of 1-cm cerrobend could reduce CBCT doses down to 31%, 51%, 68%, and 82%, respectively, for 60, 80, 100, and 125 kV when the testes lay within the CBCT field. CONCLUSIONS: Generally speaking, kVCBCT deposits much larger doses to critical structures in children than in adults, usually by a factor of 2 to 3. Increasing the distances from OARs to CBCT field border greatly reduces doses to OARs. Depending on OARs, kVCBCT-induced doses increase linearly or exponentially with photon beam energy. Testicular shielding works more efficiently at lower kV energies. On the basis of our study, it is essential to choose an appropriate scanning protocol when kVCBCT is applied to pediatric cancer patients routinely.

Thallium-201SPECT assessment in the detection of recurrences of treated gliomas and ependymomas.

INTRODUCTION: The aim of this study was to establish the value of thalium-(201) single-photon emission computed tomography ((201)Tl-SPECT) in the detection of recurrences in the follow-up of patients with treated primary neuroepithelial tumours. MATERIAL AND METHODS: Sixty-three (201)Tl-SPECT were performed in 36 patients with glioma (12 males, mean age of 46 +/- 13 years). All patients underwent surgery and adjuvant radiotherapy (and some of them received chemotherapy). All patients were submitted to morphological neuroimaging techniques as well (and (201) Tl-SPECT). Mean follow-up was 18.3 +/- 14.6 months. Gold standard was based on clinical follow-up, therapeutical decisions (at least 4 months after (201)Tl-SPECT) and imaging features. RESULTS: Sensitivity and specificity of (201)Tl-SPECT to detect glioma recurrences were 90% and 100% respectively and 93% accuracy. Sensitivity and specificity for high grade tumours, were 100% respectively. Due to 4 false negatives, sensitivity and specificity for low grade gliomas were 78% and 100%. In the positive (201)Tl-SPECT group of patients overall survival was 13.64% at the end of the study. The negative (201)Tl-SPECT group had 84.62% overall survival at the end of the study (p = 0.0003). CONCLUSIONS. (201)Tl-SPECT is a valuable and noninvasive diagnostic procedure to detect recurrence or progression disease for treated gliomas and ependymomas. (201)Tl-SPECT has a good correlation with short term prognosis with excellent diagnostic accuracy.

Brain tumours under the age of three. The price of survival. A retrospective study of 20 long-term survivors.

Between 1975 and 1989, 98 children with brain tumours under the age of three at time of diagnosis were entered into a retrospective study. Twenty of them are alive and free of tumour more than five years after treatment and were evaluated in this study. Thirteen tumour localizations were infratentorial and 7 were supratentorial. A histological examination was performed in 15 patients: 5 ependymomas, 6 medulloblastomas and 4 astrocytomas were identified. Fifteen patients underwent surgical removal of tumour, all but one received radiotherapy and 8 were given chemotherapy. Only two children have not late effects. Analysis of long-term sequelae in survivors showed central endocrinopathies in 14 (70%), a neurological handicap in 13 (65%) and impaired cognitive functions in 17 (85%). Irradiation was clearly responsible for mental sequelae in 7 patients and endocrinopathies in 6 patients. The other possible causes are tumour injury, hydrocephalus or surgery. The risks incurred with radiotherapy and advances in infant brain tumour therapy are discussed.