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.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

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.

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.

[Magnetic resonance and computerized tomography of posterior cranial fossa tumors in childhood. Differential diagnosis and assessment of lesion extent]. / Risonanza magnetica e tomografia computerizzata dei tumori della fossa cranica posteriore nell'età pediatrica. Diagnosi differenziale e bilancio di estensione.

In the last thirty years much progress has been made in the treatment of brain tumors in children, thanks to modern diagnostic imaging techniques, together with neurosurgery and radiotherapy, for the diagnosis and follow-up of these lesions. MRI and paramagnetic contrast agents have revolutionized the imaging of intracranial conditions, especially in the posterior cranial fossa. The superiority of MRI over CT is well known and reported in the literature, but the adequacy of the two methods has rarely been compared. Therefore, this study was aimed at assessing and quantitating the accuracy of MRI and CT relative to two essential parameters: preoperative "histologic" diagnosis and local and distant intracranial tumor extent. In 52 selected patients the final histologic diagnosis was cerebellar medulloblastoma in 20 cases, cerebellar astrocytoma in 12 cases, brain stem glioma in 12 cases and ependymoma in 8 cases. CT allowed the correct diagnosis to be made in 25 patients (48%), with questionable findings in 21 patients (40%) and 6 misdiagnoses (12%). MRI allowed the correct diagnosis to be made in 43 patients (83%), with questionable findings in 9 patients (17%) and no misdiagnoses. MRI depicted local and distant tumor spread in 34 patients while CT showed it in 22 patients only. The analysis of the results confirmed the superiority of MRI over CT, relative to the parameters considered, i.e. histology and the assessment of tumor spread. In the clinical suspicion of brain tumors of the posterior cranial fossa in children, MRI--if available--should be the examination of choice if the patient's clinical status does not prevent its use. CT should be used only in emergency cases (acute intracranial hypertension) to identify hydrocephalus and intratumoral hemorrhages. Unenhanced CT also yields useful pieces of information for lesion "histology" and may be used to integrate MR findings in selected cases.