Characterization and clinical validation of patient-specific three-dimensional printed tissue-equivalent bolus for radiotherapy of head and neck malignancies involving skin.

PURPOSE: Megavoltage radiotherapy to irregular superficial targets is challenging due to the skin sparing effect. We developed a three-dimensional bolus (3DB) program to assess the clinical impact on dosimetric and patient outcomes. MATERIALS AND METHODS: Planar commercial bolus (PCB) and 3DB density, clarity, and net bolus effect were rigorously evaluated prior to clinical implementation. After IRB approval, patients with cutaneous or locally advanced malignancies deemed to require bolus for radiotherapy treatment were treated with custom 3DB. RESULTS: The mean density of 3DB and PCB was of 1.07 g/cm 3 and 1.12 g/cm3, respectively. 3DB optic clarity was superior versus PCB at any material thickness. Phantom measurements of superficial dose with 3DB and PCB showed excellent bolus effect for both materials. 3DB reduced air gaps compared with PCB - particularly in irregular areas such as the ear, nose, and orbit. A dosimetric comparison of 3DB and PCB plans showed equivalent superficial homogeneity for 3DB and PCB (3DB median HI 1.249, range 1.111-1.300 and PCB median HI 1.165, range 1.094-1.279), but better conformity with 3DB (3DB median CI 0.993, range 0.962-0.993) versus PCB (PCB median CI 0.977, range 0.601-0.991). Patient dose measurements using 3DB confirm the delivered superficial dose was within 1% of the intended prescription (95% CI 97-102%; P = 0.11). CONCLUSIONS: 3DB improves radiotherapy plan conformity, reduces air gap volume in irregular superficial areas which could affect superficial dose delivery, and provides excellent dose coverage to irregular superficial targets.

Linear Accelerator-Based Radiotherapy Simulation Using On-Board Kilovoltage Cone-Beam Computed Tomography for 3-Dimensional Volumetric Planning and Rapid Treatment in the Palliative Setting.

BACKGROUND: Palliation of advanced disease using radiotherapy can create difficult clinical situations where standard computed tomography simulation and immobilization techniques are not feasible. We developed a linear accelerator-based radiotherapy simulation technique using nonstandard patient positioning for head and neck palliation using on-board kilovoltage cone-beam computed tomography for 3-D volumetric planning and rapid treatment. Material and Methods: We proved cone-beam computed tomography simulation feasibility for semi-upright patient positioning using an anthropomorphic phantom on a clinical Elekta-Synergy linear accelerator. Cone-beam computed tomography imaging parameters were optimized for high-resolution image reconstruction and to ensure mechanical clearance. The patient was simulated using a cone-beam computed tomography-based approach and the cone-beam computed tomography digital imaging and communications in medicine file was imported to the treatment planning software to generate radiotherapy target volumes. Rapid planning was achieved by using a 3-level bulk density correction for air, soft tissue, and bone set at 0, 1.0, and 1.4 g/cm3, respectively. RESULTS: Patient volumetric imaging was obtained through cone-beam computed tomography simulation and treatment was delivered as planned without incident. Bulk density corrections were verified against conventionally simulated patients where differences were less than 1%. Conclusion: We successfully developed and employed a semi-upright kilovoltage cone-beam computed tomography-based head and neck simulation and treatment planning method for 3-D conformal radiotherapy delivery. This approach provides 3-D documentation of the radiotherapy plan and allows tabulation of quantitative spatial dose information which is valuable if additional palliative treatments are needed in the future. This is a potentially valuable technique that has broad clinical applicability for benign and palliative treatments across multiple disease sites-particularly where standard supine simulation and immobilization techniques are not possible.

Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies.

PURPOSE: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. EXPERIMENTAL DESIGN: We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. RESULTS: In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. CONCLUSIONS: These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR.

Anthropomorphic Phantoms for Confirmation of Linear Accelerator-Based Small Animal Irradiation.

Three dimensional (3D) scanning and printing technology is utilized to create phantom models of mice in order to assess the accuracy of ionizing radiation dosing from a clinical, human-based linear accelerator. Phantoms are designed to simulate a range of research questions, including irradiation of lung tumors and primary subcutaneous or orthotopic tumors for immunotherapy experimentation. The phantoms are used to measure the accuracy of dose delivery and then refine it to within 1% of the prescribed dose.

Patterns-of-care for thoracic stereotactic body radiotherapy among practicing radiation oncologists in the United States.

INTRODUCTION: Radiation oncologists were surveyed to assess practice patterns in the use of stereotactic body radiotherapy (SBRT) for lung cancer. METHODS: A customized patterns-of-care survey, consisting of 18 questions and two clinical scenarios, was e-mailed to 136 academic radiation oncologists and 768 community practitioners to evaluate the technical basis and delivery parameters associated with SBRT. RESULTS: A total of 117 surveys were evaluable. The cited delivery techniques included: static noncoplanar beams (48%), intensity-modulated radiotherapy (41%), rotational intensity-modulated radiotherapy (47%), dynamic conformal arcs (7%), and small-beam delivery with fiducial tracking (24%), with 46% using multiple techniques. The immobilization methods included: stereotactic frame (10%), alpha cradle or vacuum-lock system (52%), wingboard (3%), stereotactic frame with an alpha cradle or vacuum-lock system (11%); combination of devices (14%), or no immobilization (9%). Abdominal compression was used by 51% and respiratory gating by 31%. For a peripheral T1N0 tumor, the preferred doses included: 25 to 34 Gy in one fraction (1%); 54 to 60 Gy in three fractions (56%), 48 to 50 Gy in four fractions (18%), and 50 to 60 Gy in five fractions (25%). For a centrally located T1N0 tumor, 58% recommended SBRT outside a clinical protocol, with recommended doses ranging from 40 to 60 Gy in three to 10 fractions. The recommended interval to first surveillance imaging ranged from 6 weeks or lesser (32%) to 25 weeks or more (2%). CONCLUSIONS: Considerable variation exists for thoracic SBRT with regard to dose selection, fractionation, immobilization, planning, management of central lesions, and surveillance. Ongoing prospective evaluation is recommended to identify best practices and provide continual process improvement.

Failure mode and effect analysis for delivery of lung stereotactic body radiation therapy.

PURPOSE: To improve the quality and safety of our practice of stereotactic body radiation therapy (SBRT), we analyzed the process following the failure mode and effects analysis (FMEA) method. METHODS: The FMEA was performed by a multidisciplinary team. For each step in the SBRT delivery process, a potential failure occurrence was derived and three factors were assessed: the probability of each occurrence, the severity if the event occurs, and the probability of detection by the treatment team. A rank of 1 to 10 was assigned to each factor, and then the multiplied ranks yielded the relative risks (risk priority numbers). The failure modes with the highest risk priority numbers were then considered to implement process improvement measures. RESULTS: A total of 28 occurrences were derived, of which nine events scored with significantly high risk priority numbers. The risk priority numbers of the highest ranked events ranged from 20 to 80. These included transcription errors of the stereotactic coordinates and machine failures. CONCLUSION: Several areas of our SBRT delivery were reconsidered in terms of process improvement, and safety measures, including treatment checklists and a surgical time-out, were added for our practice of gantry-based image-guided SBRT. This study serves as a guide for other users of SBRT to perform FMEA of their own practice.

Comparison of peripheral dose from image-guided radiation therapy (IGRT) using kV cone beam CT to intensity-modulated radiation therapy (IMRT).

PURPOSE: The growing use of IMRT with volumetric kilovoltage cone-beam computed tomography (kV-CBCT) for IGRT has increased concerns over the additional (typically unaccounted) radiation dose associated with the procedures. Published data quantify the in-field dose of IGRT and the peripheral dose from IMRT. This study adds to the data on dose outside the target area by measuring peripheral CBCT dose and comparing it with out-of-field IMRT dose. MATERIALS AND METHODS: Measurements of the CBCT peripheral dose were made in an anthropomorphic phantom with TLDs and were compared to peripheral dose measurements for prostate IMRT, determined with MOSFET detectors. RESULTS: Doses above 1cGy (per scan) were found outside the CBCT imaged volume, with 0.2cGy at 25 cm from the central axis. IMRT peripheral dose was 1cGy at 20 cm and 0.4cGy at 25 cm (per fraction). CONCLUSIONS: An appreciable dose can be found beyond the edge of the IGRT field; of similar order of magnitude as peripheral dose from IMRT (mGy), and approximately half the dose delivered to the same point from the IMRT treatment (0.2cGy c.f. 0.4cGy 25 cm from the isocenter). This shows that peripheral dose, as well as the in-field dose from CBCT, needs to be taken into account when considering long term care of radiation oncology patients.

The option of Linac-based radiosurgery in a Gamma Knife radiosurgery center.

OBJECTIVE: Due to the fundamental differences in treatment delivery, linear-accelerator-based radiosurgery can be complementary to Gamma Knife (GK) for intracranial lesions. We reviewed the effect of adding GK to an existing linear accelerator (Linac)-based radiosurgery practice and analyzed case selections for the two modalities. PATIENTS AND METHODS: UC Davis Medical Center installed a Leksell Gamma Knife Model C in October 2003 to supplement an established Linac-based radiosurgery program. Radiosurgery indications for the 15 months before and after installation were compared. RESULTS: Radiosurgery cases expanded by twofold from 68 patients before GK installation to 139 after, with 106 treated by GK and 33 by Linac. Besides a major increase for trigeminal neuralgia and a general growth for acoustic neuroma, meningioma and brain metastases, case numbers for glioma and arteriovenous malformation (AVM) remained stable. Considering case selections for Linac, glioma decreased from 28 to 18%, while meningioma and metastases increased from 9 to 21% and 38-46%, respectively. The Linac patients receiving fractionated treatment also increased from 37 to 61%. CONCLUSIONS: While the majority of patients were treated with GK, a significant proportion was judged to be suited for Linac treatment. This latter group included particularly patients who benefit from fractionated therapy.

Clinical impact of magnetic resonance imaging on Gamma Knife surgery for brain metastases.

OBJECT: Stereotactic radiosurgery is beneficial for patients with a limited number of small brain metastases. Increased numbers of brain metastases, not infrequently at unreachable locations, are identified using thin-section magnetic resonance (MR) imaging on the day of Gamma Knife surgery (GKS). To improve patient selection and design better treatment strategies, a retrospective study was conducted to determine factors that may contribute to detecting additional brain metastases on the day of GKS. METHODS: A total of 100 patients with brain metastases who underwent GKS between October 2003 and May 2006 at the University of California Davis Medical Center were included in the present study. Patients were categorized by age, sex, Karnofsky Performance Scale score, status of systemic disease, histological characteristics of the primary tumor, and whether they received previous whole-brain radiotherapy (WBRT). The number of lesions identified by diagnostic MR imaging at referral, by thin-section double-contrast MR imaging on the day of GKS, and the actual lesions treated by GKS were recorded. The diagnostic MR images were categorized in terms of section thickness and time interval before GKS. CONCLUSIONS: The characteristics of this patient population match well with the general GKS practice. Fifty-six had been treated with WBRT. On average, patients presented with 2.2 +/- 1.7 lesions, a number based on their original diagnostic MR imaging, had 3.6 +/- 3.4 lesions identified on the thin-section treatment MR imaging (p < 0.05), and underwent treatment of 3.1 +/- 2.6 lesions on the day of GKS. Significantly, treatment was compromised in 21 patients, in whom not all additional lesions could be treated with the initial headframe placement. Analysis shows that a significantly greater number of lesions were detected using thin-section MR imaging on the day of GKS in patients who had undergone thick-section diagnostic MR imaging, did not receive WBRT, and had progressive systemic disease. To optimize treatment planning and minimize additional treatment, the number of metastases needs to be determined accurately before frame placement, ideally by performing thin-section MR imaging, as used on the day of GKS.

Linear accelerator-based radiosurgery for multiple arteriovenous malformations: case report.

This report presents a rare case of multiple, widely spaced arteriovenous malformations in a single patient treated with linear accelerator-based radiosurgery. The choices associated with the requisite imaging and planning are presented. In light of the anatomic topography, linear accelerator-based radiosurgery was chosen over gamma knife treatment, with CT angiography being used to image all target areas simultaneously.