Stereotactic Proton Research Articles

Immunohistochemical Verification of Stereotactic Proton Radiosurgery Targeting Accuracy in the Rat Brain

We have developed a system for targeting functional areas in the rat brain with narrow proton beams. Due to the extremely sharp lateral dose falloff of high-energy proton beams, a cross-fire technique with multiple shoot-through beams converging on the target will be used to selectively irradiate small regions in the rat brain. The spatial accuracy of dose delivery is crucial and needs to be verified. This ongoing study intends to verify the accuracy and precision of the targeting method by developing immunohistochemical staining protocols based on IgG leakage through the radiation-induced breakdown of the blood-brain barrier (BBB) and various DNA damage markers. Male Sprague-Dawley (8 weeks, 150-190g) rats were subjected to hemispheric proton irradiation with 250 MeV proton beams at doses of 0 Gy, 8 Gy, and 25 Gy. IgG extravasation was used to show BBB damage from 4 to 72 hours after irradiation. Rat brains perfused with 4% paraformaldehyde-perfused were cryostat-sectioned and slide-mounted. Sections then underwent immunohistochemical staining using the ABC method (Santa Cruz Biotechnology). Radiation-induced H2AX phosphorylation, a sensitive marker of DNA double strand breaks (DSBs), was detected by Donkey anti-mouse IgG Alexa Fluor 488 (green), while nuclei were counterstained with propidium iodide (PI, red). After 25 Gy proton irradiation, radiation-induced BBB damage resulted in IgG extravasation as indicated by positive immunostaining for anti-IgG. Detection of γH2AX was also possible after hemibrain proton irradiation with 8 Gy. IgG staining is sensitive to local vascular radiation damage, which has the advantage of being maintained during longer time intervals (days to weeks rather than hours) compared to short-term DNA damage markers. The DSB marker γH2AX can be used for rapid confirmation of the targeted area. IgG staining and γH2AX immunofluorescences are useful for microscopic verification of the targeting accuracy of small-animal radiosurgery procedures with sub-millimeter resolution.

Long Term Results of Stereotactic Proton Beam Therapy for AVMs, Meningiomas, and Acoustic Neuromas

Long Term Results of Stereotactic Proton Beam Therapy for AVMs, Meningiomas, and Acoustic Neuromas

Long-term results of stereotactic proton beam radiotherapy for acoustic neuromas

Background and purpose A retrospective study evaluating the role of hypofractionated stereotactic proton beam therapy for acoustic neuromas. Materials and methods The data of 51 patients treated with hypofractionation (3 fractions) and followed up for a minimum of 2 years, were analyzed. Mean dose prescribed to ICRU reference point (isocenter) was 26 cobalt gray equivalent (CGyE) in 3 fractions. Mean minimum tumor dose was 21.4 CGyE/3. Cranial nerve functions were evaluated clinically. Serial MR Scans were used to evaluate local control. Results With a mean clinical and radiological follow-up of 72 and 60 months respectively, the 5-year results showed a 98% local control, with a hearing preservation of 42%, a facial nerve preservation of 90.5% and a trigeminal nerve preservation of 93%. Conclusion For those patients harboring large acoustic neuromas that are inoperable, hypofractionated stereotactic proton beam offers long-term control with minimal side-effects.

Management of Recurrent and Refractory Cushing's Disease with Reoperation and/or Proton Radiosurgery

Aghi, Manish K. M.D., Ph.D.; Petit, Josh; Chapman, Paul; Loeffler, Jay; Klibanski, Anne; Biller, Beverly; Swearingen, Brooke

Hyperacute Neuropathological Findings after Proton Beam Radiosurgery of the Rat Hippocampus

To study the hyperacute histological and immunohistochemical effects of stereotactic proton beam irradiation of the rat hippocampus. Nine rats underwent proton beam radiosurgery of one hippocampus with nominal doses of cobalt-2, -12, and -60 Gray equivalents (n = 3 each). Control animals (n = 3) were not irradiated. Animals were killed 5 hours after irradiation and brain sections were stained for Nissl, silver degeneration, deoxyribonucleic acid (DNA) fragmentation (DNAF), and the activated form of two mitogen-activated protein kinases (MAPKs), phospho-Erk1/2 (P-Erk1/2) and p38. Stained cells in the hippocampus expressing DNAF and/or P-Erk1/2 were counted. Confocal microscopy with double immunofluorescent staining was used to examine cellular colocalization of DNAF and P-Erk1/2. Both DNAF and P-Erk1/2 showed quantitative dose-dependent increases in staining in the targeted hippocampus compared with the contralateral side and controls. This finding was restricted to the subgranular proliferative zone of the hippocampus. Both markers also were up-regulated on the contralateral side when compared with controls in a dose-dependent fashion. Simultaneous staining for DNAF and P-Erk1/2 was found in fewer than half of all cells. p38 was unchanged compared with controls. Although Nissl staining appeared normal, silver stain confirmed dose-dependent cellular degeneration. DNAF, a marker of cell death, was present in rat hippocampi within 5 hours of delivery of cobalt-2 Gray equivalents stereotactically focused irradiation, suggesting that even low-dose radiosurgery has hyperacute neurotoxic effects. Activated mitogen-activated protein kinase was incompletely colocalized with DNAF, suggesting that activation of this cascade is neither necessary nor sufficient to initiate acute cell death after irradiation.

TU-C-T-617-10: The Use of a Miniature Multileaf Collimator in Stereotactic Proton Therapy

Purpose: To evaluate — in terms of dose conformity, neutron dose, activation, and leakage — the use of a Miniature Multileaf Collimator (MMLC) in stereotactic proton therapy, both as an aperture and for segmented intensity modulated proton therapy (IMPT). Method and Materials: Firstly, we compute the neutron production and activation of the MMLC with Geant4. In a simple geometry — a cylindrical target hit by a pencil proton beam — we determine the neutron distribution as function of position and energy, and compare tungsten,brass,nickel, and lead. Given the point‐spread functions, we assess the secondary‐neutron dose to the patient for the different materials and MMLC distance to patient. Secondly, we model the Radionics ConforMAX™ MMLC as integrated in our stereotactic proton beamline, and compare the dose distributions for the MMLC and an equivalent aperture. The results are validated with radiographic film measurements. Finally, we measure the proton leakage, activation, and neutron dose. Results: The neutron production in tungsten, the leaf material in most MLC's, is more than twice that of nickel. For a 10 cm diameter field, with a range of 15 g/cm2 and modulation of 5 g/cm2, and with the MMLC positioned at 30.0 cm from the patient, the maximum neutron dose, i.e. for a closed MLC, is ∼0.04% of the target dose. The MMLC leaf width at iso center is 3.2 mm; the lateral penumbra in air is 0.6 mm. Conclusion: In beam‐lines with a large SAD, such as our stereotactic beam‐line, the use of the MMLC as aperture is feasible. The device can be positioned far away from the patient, which reduces the neutron dose to acceptable levels, while hardly compromising the lateral penumbra. Given a decrease in proton efficiency of a factor of 3, the MMLC could also be used for IMPT.

SU-FF-T-343: Focal Stereotactic Proton Irradiation: Micro CT Planning and Assessment by MR Spectroscopy

Purpose: Develop focal stereotactic proton irradiation for accurate spatial localization (< 2mm) in the rodent brain. Planning and evaluation was performed using Micro‐Computed Tomography(CT) and magnetic resonance spectroscopy (MRS). Method and Materials: Rodents were visualized using Micro‐CT; the data was transferred to Optirad (protontreatment planning system) for planning the site of brain irradiation (20 Gy). After irradiation the animals were positioned for protonmagnetic resonance spectroscopy (MRS) on a 4.7T imager. Acquisition conditions for metabolite assessment allowed complete relaxation between excitations. A 5 mm3 voxel was placed at the irradiation site. Care was taken to avoid bone‐tissue interfaces. The MRS data was collected into 2048 points (frequency resolution of 1.2 Hz/point), a relaxation delay of 4s and an echo time of 120ms. A water presupression pulse reduced the water peak below 1%. The MRS acquisition parameters were; a field of view of 5 cm, two acquisitions, a matrix size of 256 × 128 for a total imaging time of 8.5min. Results: At 12 hrs after focal irradiation, MRS revealed the presence of a lactate (Lac) peak that did not resolve during the course of the 5‐day imaging series. In addition, the peak height of N‐acetyl‐aspartate (NAA) was reduced at 12 hrs compared to choline (Cho) and creatine (Cre) peaks. The NAA changes relative to Cho/Cre appeared to resolve over the 5 day time course. Conclusion: Focal stereotactic proton irradiation (<2mm) can be obtained when combined with CT and MRS. Validation of high dose focal irradiation by MRS suggested cellular injury as evidenced by a persistent lactate peak, indicative that cellular necrosis continues for at least five days. Transient neuronal injury was shown by reduced NAA/(Cho+Cre) at 12h with a partial recovery over the next five days. Histology was performed to further validate these findings.

Stereotactic proton beam therapy for intracranial arteriovenous malformations

To investigate hypofractionated stereotactic proton therapy of predominantly large intracranial arteriovenous malformations (AVMs) by analyzing retrospectively the results from a cohort of patients. Since 1993, a total of 85 patients with vascular lesions have been treated. Of those, 64 patients fulfilled the criteria of having an arteriovenous malformation and sufficient follow-up. The AVMs were grouped by volume: <14 cc (26 patients) and > or =14 cc (38 patients). Treatment was delivered with a fixed horizontal 200 MeV proton beam under stereotactic conditions, using a stereophotogrammetric positioning system. The majority of patients were hypofractionated (2 or 3 fractions), and the proton doses are presented as single-fraction equivalent cobalt Gray equivalent doses (SFEcGyE). The overall mean minimum target volume dose was 17.37 SFEcGyE, ranging from 10.38-22.05 SFEcGyE. Analysis by volume group showed obliteration in 67% for volumes <14 cc and 43% for volumes > or =14 cc. Grade IV acute complications were observed in 3% of patients. Transient delayed effects were seen in 15 patients (23%), becoming permanent in 3 patients. One patient also developed a cyst 8 years after therapy. Stereotactic proton beam therapy applied in a hypofractionated schedule allows for the safe treatment of large AVMs, with acceptable results. It is an alternative to other treatment strategies for large AVMs. AVMs are likely not static entities, but probably undergo vascular remodeling. Factors influencing angiogenesis could play a new role in a form of adjuvant therapy to improve on the radiosurgical results.

230 Oral Intensity modulated stereotactic therapy and proton therapy: a study of dose conformation for cranial lesion

230 Oral Intensity modulated stereotactic therapy and proton therapy: a study of dose conformation for cranial lesion

Stereotactic proton radiosurgery in the management of persistent acromegaly

Stereotactic proton radiosurgery in the management of persistent acromegaly

Stereotactic proton beam radiosurgery for ACTH producing adenomas in the MRI/CT era

Background: Proton radiosurgery has been used for ablating pituitary adenomas with variable success based on X-ray location of the sella since the 1960’s. However, the marriage of MRI imaging with CT planning has further allowed the precise localization of the treatment volume. In addition, better dosimetry and techniques of spreading out the Bragg peak have markedly improved proton radiosurgery by increasing the dose homogeneity.

Stereotactic proton beam therapy of skull base meningiomas

Purpose: To review outcomes for patients with skull base meningiomas treated using the stereotactic proton beam at the National Accelerator Center (NAC), Republic of South Africa. Methods and Materials: Since 1993, 27 patients with intracranial meningiomas have been treated stereotactically with protons at NAC. Of those, 23 were located on the skull base, were large or had complex shapes, and were treated with radical intent. Both stereotactic radiotherapy (SRT, 16 or more fractions) and hypofractionated stereotactic radiotherapy (HSRT, 3 fractions) were used. Eighteen patients underwent proton HSRT, while 5 patients were treated with SRT. The mean target volume for the HSRT group was 15.6 cm 3 (range 2.6–63 cm 3). The mean ICRU reference dose was 20.3 cobalt Gray equivalent (CGyE), and the mean minimum planning target dose was 16.3 CGyE. The mean clinical and radiologic follow-up periods were 40 and 31 months respectively. The mean volume in the SRT group was 43.7 cm 3, with ICRU reference doses ranging from 54 CGyE in 27 fractions to 61.6 CGyE in 16 fractions. Results: In the HSRT group, 16/18 (89%) of patients remained clinically stable or improved, while 2/18 (11%) deteriorated. Radiologic control was achieved in 88% of patients, while 2 patients had a marginal failure. Among the 5 SRT patients, 2 were clinically better, and 3 remained stable. All SRT patients achieved radiologic control. Three patients (13%), 2 of them in the HSRT group, suffered permanent neurologic deficits. Analyzing different dose/fractionation schedules, an α/β value of 3.7 Gy for meningiomas is estimated. Conclusion: Proton irradiation is effective and safe in controlling large and complex-shaped skull base meningiomas.

Stereotactic Proton Radiosurgery

The technique of stereotactic proton radiosurgery is discussed in depth in this article. The physics of the proton beam in radiosurgery is explained, and the different factors of beam delivery are examined. These key factors (correspondence to shape, accuracy of delineation of volume, correspondence to volume, and accuracy of delivery vary) with each of the radiosurgical techniques, from Gamma Knife surgery to linear accelerator therapy. Clinical series in the use of proton radiosurgery are also presented, with an emphasis on efficacy and uses.

Computed tomography slice-by-slice target-volume delineation for stereotactic proton irradiation of large intracranial arteriovenous malformations: an iterative approach using angiography, computed tomography, and magnetic resonance imaging

: Target-volume delineation for stereotactic irradiation is problematic for large and irregularly shaped arteriovenous malformations (AVMs). The purpose of this report is to quantify modifications in the target volume hat result from iterative treatment planning that incorporates multimodality imaging data. : Stereotactic neuroimaging procedures were performed for 20 consecutive patients with AVM volumes > 10 cm3. Angiographically defined extrema were transformed into computed tomography (CT) space. The resulting target contours were then modified by a multidisciplinary treatment planning team after iterative review of angiographic, CT, and magnetic resonance imaging (MRI) data. Volumes of interest and dose-volume histograms for proton irradiation were calculated before and after iterative target delineation. : Initial (angiographically defined) target volumes ranged from 15.3 to 96.1 cm3 (mean, 43.6 cm3). Final (iteratively defined) target volumes ranged from 10.7 to 114.0 cm3 (mean, 38.4 cm3). The volume of presumed normal tissue excluded by iterative planning ranged from 2.6 to 47.0 cm3 (mean, 15.5 cm3). Initially untargeted AVM, most commonly obscured by embolization material, was identified in all cases (range, 0.3 to 57.8 cm3; mean, 10.3 cm3). Corresponding dose-volume histograms demonstrated marked differences regarding lesion coverage and sparing of normal tissue structures. : Iterative target-volume delineation resulted in significant modifications from initial, angiographically defined target volumes. Substantial amounts of apparently normal tissue were excluded from the final target, and additional abnormal vascular structures were identified for incorporation. We conclude that an iterative multimodality approach to target-volume delineation may improve the overall results for stereostatic irradiation of large and complex AVMs.

Computed tomography slice-by-slice target-volume delineation for stereotactic proton irradiation of large intracranial arteriovenous malformations: An iterative approach using angiography, computed tomography, and magnetic resonance imaging

Purpose : Target-volume delineation for stereotactic irradiation is problematic for large and irregularly shaped arteriovenous malformations (AVMs). The purpose of this report is to quantify modifications in the target volume hat result from iterative treatment planning that incorporates multimodality imaging data. Methods and Materials : Stereotactic neuroimaging procedures were performed for 20 consecutive patients with AVM volumes > 10 cm 3. Angiographically defined extrema were transformed into computed tomography (CT) space. The resulting target contours were then modified by a multidisciplinary treatment planning team after iterative review of angiographic, CT, and magnetic resonance imaging (MRI) data. Volumes of interest and dose-volume histograms for proton irradiation were calculated before and after iterative target delineation. Results : Initial (angiographically defined) target volumes ranged from 15.3 to 96.1 cm 3 (mean, 43.6 cm 3). Final (iteratively defined) target volumes ranged from 10.7 to 114.0 cm 3 (mean, 38.4 cm 3). The volume of presumed normal tissue excluded by iterative planning ranged from 2.6 to 47.0 cm 3 (mean, 15.5 cm 3). Initially untargeted AVM, most commonly obscured by embolization material, was identified in all cases (range, 0.3 to 57.8 cm 3; mean, 10.3 cm 3). Corresponding dose-volume histograms demonstrated marked differences regarding lesion coverage and sparing of normal tissue structures. Conclusions : Iterative target-volume delineation resulted in significant modifications from initial, angiographically defined target volumes. Substantial amounts of apparently normal tissue were excluded from the final target, and additional abnormal vascular structures were identified for incorporation. We conclude that an iterative multimodality approach to target-volume delineation may improve the overall results for stereostatic irradiation of large and complex AVMs.

A precision cranial immobilization system for conformal stereotactic fractionated radiation therapy

Conformal radiotherapy has been shown to benefit from precision alignment of patient target to therapy beam (1, 6, 13). This work describes an optimized immobilization system for the fractionated treatment of intracranial targets. A study of patient motion demonstrates the high degree of immobilization which is available. A system using dental fixation and a thermoplastic mask that relocates on a rigid frame is described. The design permits scanning studies using computed tomography (CT) and magnetic resonance imaging (MR), conventional photon radiotherapy, and high precision stereotactic proton radiotherapy to be performed with minimal repositioning variation. Studies of both intratreatment motion and daily setup reliability are performed on patients under treatment for paranasal sinus carcinoma. Multiple radiographs taken during single treatments provide the basis for a three-dimensional (3D) motion analysis. Additionally, studies of orthogonal radiographs used to setup for proton treatments and verification port films from photon treatments are used to establish day to day patient position variation in routine use. Net 3D patient motion during any treatment is measured to be 0.9 +/- 0.4 mm [mean +/- standard deviation (SD)] and rotation about any body axis is 0.14 +/- 0.67 degrees (mean +/- SD). Day-to-day setup accuracy to laser marks is limited to 2.3 mm (mean) systematic error and 1.6 mm (mean) random error. We conclude that the most stringent immobilization requirements of 3D conformal radiotherapy adjacent to critical normal structures can be met with a high precision system such as the one described here. Without the use of pretreatment verification, additional developments in machine and couch design are needed to assure that patient repositioning accuracy is comparable to the best level of patient immobility achievable.

Clinical and radiological evaluation of long-term results of stereotactic proton beam radiosurgery in patients with cerebral arteriovenous malformations

Within a period of nearly 10 years, from October, 1980, to May, 1990, a total of 68 patients with a cerebral arteriovenous malformation (AVM) were referred to a radiosurgical center in the United States for stereotactic Bragg peak proton beam therapy. Radiosurgery was chosen as an alternative treatment, either because the AVM was considered to be of high surgical risk due to its size and/or location, or because the patient refused surgery. In 63 patients (92.6%), complete clinical and radiological follow-up examinations were available. Clinical and radiological long-term results were correlated to size and to the Spetzler-Martin scale of the AVM. With increasing size or higher grade on the Spetzler-Martin scale, the clinical results of proton beam therapy became progressively worse. Of 37 patients with an AVM between 3 and 6 cm in diameter, only one-third showed amelioration of their clinical symptoms, and two-thirds remained the same or even deteriorated after radiation treatment. The same results apply to patients with very large AVM's, of whom only one-third profited from proton beam therapy. Although 85.7% of the patients in Spetzler-Martin Grades I and II showed postirradiation amelioration of their clinical symptoms, this compares to only 54.2% of the patients in Grade III, and only 24% in Grade IV. In regard to the radiological results of proton beam therapy, complete obliteration during long-term observation was only detectable in 10 patients or 15.9%, which is less than one-sixth of the whole group of 63 patients. All of these obliterated AVM's were smaller than 3 cm. Almost 85% of the patients treated using stereotactic proton beam therapy did not show any angiographic change in the radiological appearance of their AVM. The results reported here indicate that radiosurgery using stereotactic proton beam therapy is ineffective for the treatment of medium- or large-sized AVM's and should not be recommended for patients harboring an AVM larger than 3 cm. If proton beam treatment is contemplated, it should be restricted to AVM's that are less than 3 cm in size and whose location makes them easily accessible only for proton beam therapy.

A multi-institutional interactive network for stereotactic proton irradiation of intracranial arteriovenous malformations: design, implementation and initial experience

A multi-institutional interactive network for stereotactic proton irradiation of intracranial arteriovenous malformations: design, implementation and initial experience

Relief of epilepsy by radiosurgery of cerebral arteriovenous malformations.

129 patients with inoperable cerebral arteriovenous malformations (AVM) were treated by stereotactic proton beam irradiation. Symptomatic epilepsy was present in 29 patients (22.5%) before the treatment. It was markedly relieved by the radiosurgery leading to cessation of the seizures in 16 patients, the persisting seizure-free follow-up period ranging from 2 to 8 years (mean 4.5 years). In no case was the epilepsy worsened by radiosurgery. The positive effect on epilepsy was not strictly dependent on the angiographic result, suggesting that the ionizing radiation by itself could lead to inhibition of epileptic activity around the AVM.

Transposition of target information from the magnetic resonance and computed tomography scan images to conventional X-ray stereotactic space.

A technique to apply reconstructed X-ray computed tomography (CT) and magnetic resonance imaging (MRI) for target determination in stereotactic Bragg peak proton beam therapy of intracranial lesions was developed. Twenty-one benign intracranial tumors and vascular abnormalities were managed using this technique. Clinical features of these lesions, as well as targeting problems associated with the MRI and CT image interpretation, are presented.