Cranial Proton Research Articles

Modelling the influence of radiosensitivity on development of second primary cancer in out-of-field organs following proton therapy for paediatric cranial cancer.

Radiobiological modelling the risks of second primary cancer (SPC) after proton therapy (PT) for childhood cranial cancer remains largely unknown. Organ-specific dose-response risk factors such as radiosensitivity require exploration. This study compared the influence of radiosensitivity data (slope of βEAR) on children's lifetime attributable risks (LAR) of SPC development in out-of-field organs following cranial scattering and scanning PT. Out-of-field radiosensitivity parameter estimates for organs (α/β and βEAR) were sourced from literature. Physical distances for 13 out-of-field organs were measured and input into Schneider's SPC model. Sensitivity analyses were performed as a function of radiosensitivity (α/β of 1-10 Gy) and initial slope (βEAR) from Japanese/UK data to estimate the influence on the risk of radiation-induced SPC following scattering and scanning PT. Models showed similar LAR of SPC estimates for age and sex-matched paediatric phantoms, however, for breast there was a significant increase using Japanese βEAR data. For most organs, scattering PT demonstrated a larger risk of LAR for SPC which increased with α/β. Breast tissue exhibited the highest susceptibility in calculated LAR risk, demonstrating the importance for accurate data input when estimating LAR of SPC. The findings of this study demonstrated younger female patients undergoing cranial proton therapy have a higher risk of developing second primary cancer of the breast tissue. Long-term multicenter registries are important to improve predictive radiobiological modelling studies of side effects.

Three-dimensional dose and LETD prediction in proton therapy using artificial neural networks.

Challenges in proton therapy include identifying patients most likely to benefit; ensuring consistent, high-quality plans as its adoption becomes more widespread; and recognizing biological uncertainties that may be related to increased relative biologic effectiveness driven by linear energy transfer (LET). Knowledge-based planning (KBP) is a domain that may help to address all three. Artificial neural networks were trained using 117 unique treatment plans and associated dose and dose-weighted LET (LETD ) distributions. The data set was split into training (n=82), validation (n=17), and test (n=18) sets. Model performance was evaluated on the test set using dose- and LETD -volume metrics in the clinical target volume (CTV) and nearby organs at risk and Dice similarity coefficients (DSC) comparing predicted and planned isodose lines at 50%, 75%, and 95% of the prescription dose. Dose-volume metrics significantly differed (α=0.05) between predicted and planned dose distributions in only one dose-volume metric, D2% to the CTV. The maximum observed root mean square (RMS) difference between corresponding metrics was 4.3 GyRBE (8% of prescription) for D1cc to optic chiasm. DSC were 0.90, 0.93, and 0.88 for the 50%, 75%, and 95% isodose lines, respectively. LETD -volume metrics significantly differed in all but one metric, L0.1cc of the brainstem. The maximum observed difference in RMS differences for LETD metrics was 1.0keV/μm for L0.1cc to brainstem. We have devised the first three-dimensional dose and LETD -prediction model for cranial proton radiation therapy has been developed. Dose accuracy compared favorably with that of previously published models in other treatment sites. The agreement in LETD supports future investigations with biological doses in mind to enable the full potential of KBP in proton therapy.

Comparing biological effectiveness guided plan optimization strategies for cranial proton therapy: potential and challenges

BackgroundTo introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE) induced dose burden in organs at risk (OAR) while maintaining plan quality with a constant RBE.MethodsDose-optimized (DOSEopt) proton pencil beam scanning reference treatment plans were generated for ten cranial patients with prescription doses ≥ 54 Gy(RBE) and ≥ 1 OAR close to the clinical target volume (CTV). For each patient, four additional BG plans were created. BG objectives minimized either proton track-ends, dose-averaged linear energy transfer (LETd), energy depositions from high-LET protons or variable RBE-weighted dose (DRBE) in adjacent serially structured OARs. Plan quality (RBE = 1.1) was assessed by CTV dose coverage and robustness (2 mm setup, 3.5% density), dose homogeneity and conformity in the planning target volumes and adherence to OAR tolerance doses. LETd, DRBE (Wedenberg model, α/βCTV = 10 Gy, α/βOAR = 2 Gy) and resulting normal tissue complication probabilities (NTCPs) for blindness and brainstem necrosis were derived. Differences between DOSEopt and BG optimized plans were assessed and statistically tested (Wilcoxon signed rank, α = 0.05).ResultsAll plans were clinically acceptable. DOSEopt and BG optimized plans were comparable in target volume coverage, homogeneity and conformity. For recalculated DRBE in all patients, all BG plans significantly reduced near-maximum DRBE to critical OARs with differences up to 8.2 Gy(RBE) (p < 0.05). Direct DRBE optimization primarily reduced absorbed dose in OARs (average ΔDmean = 2.0 Gy; average ΔLETd,mean = 0.1 keV/µm), while the other strategies reduced LETd (average ΔDmean < 0.3 Gy; average ΔLETd,mean = 0.5 keV/µm). LET-optimizing strategies were more robust against range and setup uncertaintes for high-dose CTVs than DRBE optimization. All BG strategies reduced NTCP for brainstem necrosis and blindness on average by 47% with average and maximum reductions of 5.4 and 18.4 percentage points, respectively.ConclusionsAll BG strategies reduced variable RBE-induced NTCPs to OARs. Reducing LETd in high-dose voxels may be favourable due to its adherence to current dose reporting and maintenance of clinical plan quality and the availability of reported LETd and dose levels from clinical toxicity reports after cranial proton therapy. These optimization strategies beyond dose may be a first step towards safely translating variable RBE optimization in the clinics.

Normal tissue complication probability modeling to guide individual treatment planning in pediatric cranial proton and photon radiotherapy.

Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio. IMPT plans resulted in lower NTCP compared to IMRT across all models (p<0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (>20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p<0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p<0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p<0.0001). Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/β values.

Modelling of late side-effects following cranial proton beam therapy

BackgroundThe limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients’ quality of life. MethodsCohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed. ResultsIn the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose–response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland. ConclusionWe developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation.

A Study of Mitochondrial DNA Copy Number and Heteroplasmy in Different Rat Brain Regions after Cranial Proton Impact

A Study of Mitochondrial DNA Copy Number and Heteroplasmy in Different Rat Brain Regions after Cranial Proton Impact

NCOG-64. INCIDENCE OF EARLY OCULAR COMPLICATIONS AFTER PROTON RADIATION FOR CHILDHOOD BRAIN TUMORS

Abstract OBJECTIVES To determine the incidence, timing and risk factors of ocular complications after proton radiation (RT) in childhood brain tumor patients, to better inform screening for these complications. METHODS We performed a single-institution retrospective review of children treated with proton RT for brain tumors, with ophthalmology data available. Data abstracted included demographics, radiation details and ocular complications (cataract, dry eyes, retinal changes). RESULTS We treated 81 children with brain tumors, with protons, from 2010-18. Forty three patients with ophthalmology data available, were included in the study, with a median age of 8.3 years (y) (0.8 – 20.6y) (13 craniospinal irradiation/CSI, 27 involved-field radiation/IFRT, 3 whole ventricle). Median follow-up from end of radiation to last eye exam was 2.1y (0.2 – 7.2y). The incidence of ocular complications was 21% (9/43 patients) overall, and 62% (8/13) after CSI. Bilateral cataracts were detected at a median of 3.2y post-radiation, with incidence of 14% (6/43) overall and 38% (5/13) after CSI. Three patients underwent lens replacement. Dry eyes developed in 23% (3/13) of patients during or soon after CSI (0.04 and 0.7y post-RT). One patient with craniopharyngioma developed retinal scarring and cataracts, 2.2y and 3.5y, after IFRT. The median radiation dose to the lenses, for patients with cataract, was 26.02 Gy RBE (4 patients: 19.41 – 31.54). For 3 patients with dry eyes, the median dose (Gy RBE) was 27.93 (11.98 – 28.71) to lenses, 36.96 (25.12 – 47.49) to lacrimal glands and 30.78 (25.08 – 36.49) to corneas (mean doses to bilateral ocular structures). CONCLUSIONS Children are at risk for cataract and dry eyes after cranial protons, especially CSI, and need ophthalmology follow-up. Larger studies are needed to validate these findings and identify risk-mitigation strategies, with longer follow-up to determine the incidence of ocular complications, and functional outcomes, after cranial proton radiation.

Systematic review of the incidence and risk factors for cerebral vasculopathy and stroke after cranial proton and photon radiation for childhood brain tumors.

The aim of our study is to determine the incidence, timing, and risk factors for cerebral vasculopathy after cranial proton and photon radiation for pediatric brain tumors. We performed a single-institution retrospective review of a cohort of children treated with proton radiation for brain tumors. MRA and/or MRI were reviewed for evidence of cerebral vascular stenosis and infarcts. Twenty-one similar studies (17 photon, 4 proton) were identified by systematic literature review. For 81 patients with median follow-up of 3 years, the rates of overall and severe vasculopathy were 9.9% and 6.2% respectively, occurring a median of 2 years post radiation. Dose to optic chiasm greater than 45 Gy and suprasellar location were significant risk factors. Results were consistent with 4 prior proton studies (752 patients) that reported incidence of 5% to 6.7%, 1.5 to 3 years post radiation. With significantly longer follow-up (3.7-19 years), 9 studies (1108 patients) with traditional photon radiation reported a higher rate (6.3%-20%) and longer time to vasculopathy (2-28 years). Significant risk factors were neurofibromatosis type 1 (NF-1; rate 7.6%-60%) and suprasellar tumors (9%-20%). In 10 studies with photon radiation (1708 patients), the stroke rate was 2% to 18.8% (2.3-24 years post radiation). Childhood brain tumor survivors need screening for vasculopathy after cranial radiation, especially with higher dose to optic chiasm, NF-1, and suprasellar tumors. Prospective studies are needed to identify risk groups, and ideal modality and timing, for screening of this toxicity.

Thirteen New Patients with Guanidinoacetate Methyltransferase Deficiency and Functional Characterization of Nineteen Novel Missense Variants in theGAMTGene

Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.

Technique for sparing previously irradiated critical normal structures in salvage proton craniospinal irradiation

BackgroundCranial reirradiation is clinically appropriate in some cases but cumulative radiation dose to critical normal structures remains a practical concern. The authors developed a simple technique in 3D conformal proton craniospinal irradiation (CSI) to block organs at risk (OAR) while minimizing underdosing of adjacent target brain tissue.MethodsTwo clinical cases illustrate the use of proton therapy to provide salvage CSI when a previously irradiated OAR required sparing from additional radiation dose. The prior radiation plan was coregistered to the treatment planning CT to create a planning organ at risk volume (PRV) around the OAR. Right and left lateral cranial whole brain proton apertures were created with a small block over the PRV. Then right and left lateral “inverse apertures” were generated, creating an aperture opening in the shape of the area previously blocked and blocking the area previously open. The inverse aperture opening was made one millimeter smaller than the original block to minimize the risk of dose overlap. The inverse apertures were used to irradiate the target volume lateral to the PRV, selecting a proton beam range to abut the 50% isodose line against either lateral edge of the PRV. Together, the 4 cranial proton fields created a region of complete dose avoidance around the OAR. Comparative photon treatment plans were generated with opposed lateral X-ray fields with custom blocks and coplanar intensity modulated radiation therapy optimized to avoid the PRV. Cumulative dose volume histograms were evaluated.ResultsTreatment plans were developed and successfully implemented to provide sparing of previously irradiated critical normal structures while treating target brain lateral to these structures. The absence of dose overlapping during irradiation through the inverse apertures was confirmed by film. Compared to the lateral X-ray and IMRT treatment plans, the proton CSI technique improved coverage of target brain tissue while providing the least additional radiation dose to the previously irradiated OAR.ConclusionsProton craniospinal irradiation can be adapted to provide complete sparing of previously irradiated OARs. This technique may extend the option of reirradiation to patients otherwise deemed ineligible for further radiotherapy due to prior dose to critical normal structures.

SU‐E‐J‐76: MR Diffusion Tensor Imaging Application in Assessing Cognitive Impairment in Children After Cranial Proton Irradiation

Purpose: Magnetic resonance diffusion tensor imaging (DTI) changes may predict for cognitive impairment following cranial irradiation. We sought to assess temporal changes in white matter integrity in children with brain tumors treated with proton therapy (PT) using DTI. Methods: Six patients with low grade gliomas who had been treated with proton therapy were included. Pre‐therapy as well as the follow‐up scans (including DTI) were registered. DTI parameters were calculated and studied for changes immediately after therapy and over time. Results: In the peri‐tumoral regions which had received irradiation, FA value decreased after treatment while ADC increased over time. Within the tumor region, FA demonstrated a trend of steady increase while ADC decreased over time. Conclusions: Changes in DTI parameters were found in brain regions corresponding to higher radiation doses. In contrast, normal areas spared from excess radiation displayed no change over time. This supports the use of proton therapy for young patients. Future studies will assess patients treated with photon therapy and seek to correlate changes in imaging with cognitive outcomes.

Radiation Dose to the Lens During Craniospinal Irradiation—An Improvement in Proton Radiotherapy Technique

To evaluate the effect of angle modification of cranial field proton beam therapy on the radiation dose delivered to the lens during craniospinal irradiation (CSI). Thirty-nine patients with central nervous system tumors who received CSI with a posterior fossa boost were analyzed for the radiation dose to the lens. Thirteen patients received cranial field treatment using standard opposed-lateral proton beams, and 26 patients received treatment with angled posterior-oblique proton beams. The lens dose in a test case also was evaluated by comparing conventional X-rays with the two proton beam planning methods by using a CMS/Xio three-dimensional planning system. Substantial lens dose sparing was realized with the angling of the cranial proton beams 15 degrees -20 degrees to the posterior. In the 39 treated patients who were analyzed (median age, 7 years), average dose delivered to the lens was decreased by approximately 50% by angling of the proton beams, with the average maximum dose decreasing from 74% to 40% of the prescribed dose (p < 0.0001). Significant lens sparing was seen in patients 10 years and younger (median age, 6 years; p < 0.0001), whereas an insignificant decrease was seen in older patients (median age, 16 years; p = 0.14). With the opposed-lateral technique (median age, 6 years), the lens dose increased significantly with decreasing age (p = 0.002), whereas there was no effect of age on lens dose in the angled beam-treated group (median age, 8.5 years; p = 0.73). The present study clearly shows an advantage in sparing of the lens dose by angling the beams used during proton beam CSI. This effect is most pronounced in patients 10 years and younger because of anatomic effects of sinus development.

Depletion of high‐energy phosphates in the central nervous system of patients with systemic lupus erythematosus, as determined by phosphorus‐31 nuclear magnetic resonance spectroscopy

Systemic lupus erythematosus (SLE) can produce profound disturbances in the central nervous system, characterized by encephalopathy, focal neurologic deficits, cerebral infarction, psychosis, and seizures. We used 31P nuclear magnetic resonance (NMR) spectroscopy to determine the in vivo levels of high-energy phosphates in the central nervous system of 10 patients with SLE and 10 age-matched normal controls. 31P NMR spectroscopy was performed on a 1.5-Tesla unit equipped with a dual-tuned 1H-31P surface coil and a software-directed DRESS (depth resolved surface coil spectroscopy) pulse sequence. This procedure detected ADP, ATP, sugar phosphates, phosphocreatine (PCr), inorganic phosphate, phosphomonoesters, and phosphodiesters in the brain tissue of all study subjects. Levels of ATP in the deep white matter of 10 SLE patients were significantly decreased compared with the levels in 10 normal controls, as quantitated by the ratio of ATP:ATP + ADP (mean +/- SD 0.81 +/- 0.11 versus 0.91 +/- 0.05; P less than 0.02). In a subgroup of 4 patients, PCr levels were decreased to a greater extent than the ATP levels. NMR spectroscopic alterations were not related to obvious anatomic lesions, as determined by standard cranial proton magnetic resonance imaging. In 4 SLE patients with markedly abnormal 31P NMR spectra, treatment with prednisone (80 mg/day) normalized the levels of ATP and PCr. Restoration of a normal 31P profile was accompanied by an obvious improvement in the patients' mental status and clinical symptoms. 31P NMR spectroscopy is a powerful new technique for monitoring high-energy phosphate metabolism, and may be particularly useful for characterizing central nervous system disease in patients with neuropsychiatric SLE.