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Purpose To evaluate the accuracy of surface‐guided radiotherapy (SGRT) in cranial patient setup by direct comparison between optical surface imaging (OSI) and cone‐beam computed tomography (CBCT), before applying SGRT‐only setup for conventional radiotherapy of brain and nasopharynx cancer. Methods and Materials Using CBCT as reference, SGRT setup accuracy was examined based on 269 patients (415 treatments) treated with frameless cranial stereotactic radiosurgery (SRS) during 2018‐2019. Patients were immobilized in customized head molds and open‐face masks and monitored using OSI during treatment. The facial skin area in planning CT was used as OSI region of interest (ROI) for automatic surface alignment and the skull was used as the landmark for automatic CBCT/CT registration. A 6 degrees of freedom (6DOF) couch was used. Immediately after CBCT setup, an OSI verification image was captured, recording the SGRT setup differences. These differences were analyzed in 6DOFs and as a function of isocenter positions away from the anterior surface to assess OSI‐ROI bias. The SGRT in‐room setup time was estimated and compared with CBCT and orthogonal 2D kilovoltage (2DkV) setups. Results The SGRT setup difference (magnitude) is found to be 1.0 ± 2.5 mm and 0.1˚±1.4˚ on average among 415 treatments and within 5 mm/3˚ with greater than 95% confidence level (P 5.0mm and 9 (2.2%) are >3.0˚. The setup differences show minor correlations (|r| < 0.45) between translational and rotational DOFs and a minor increasing trend (

Objective (1) Assess the feasibility of 13 N-ammonia cardiac PET (13 N-ammonia-PET) imaging in radiotherapy (RT) treatment position in locally-advanced breast cancer (LABC) patients. (2) Correlate pre−/post-RT changes in myocardial flow reserve (MFR) with the corresponding radiation heart dose. Methods Ten left-sided LABC patients undergoing Volumetric Modulated-Arc-Therapy (VMAT) to chest wall and regional lymph nodes underwent a rest/stress 13 N-ammonia-PET at baseline and (median) 13 months post-RT. Changes in cardiac functions and coronary artery Ca2+ scoring between baseline and follow-up were correlated with average RT dose to the myocardium,3 coronary territories, and 17 myocardial segments. Results Eight (of 10) patients successfully completed the study. The average rest (stress) global MBF (ml.g-1.min-1) for baseline (follow-up) were 0.83 ± 0.25 (2.4 ± 0.79) and 0.92 ± 0.30 (2.76 ± 0.71), respectively. Differences in MBF, heart rate, blood pressure, and rate-pressure product (RPP) between baseline and follow-up were insignificant (P > 0.1).Strong (R = 0.79; P 50) for all patients in both studies. Conclusion The feasibility of 13 N-ammonia-PET imaging in treatment position of LABC patients was demonstrated. MFR at 1-year post-irradiation of the heart decreased in 50% of the patients. MFR may be a potential index for early detection of cardiotoxicity in BC patients receiving RT to the chest wall.

Purpose The implementation and evaluation of an in‐house developed geometry optimization (GO) software are described. The GO script provides optimal lesion clustering, isocenter placement, and collimator angle of each arc for cranial multi‐lesion stereotactic radiosurgery (SRS) volumetric modulated arc therapy (VMAT) planning. Materials and methods An Eclipse‐plugin program was developed to facilitate automatic plan geometry generation for multiple metastases SRS VMAT plans. A mixed, semi‐supervised exhaustive and k‐means clustering method is used to group lesions and place isocenters. The sum of squared euclidean distance (SSED) and the boundaries of lesions’ projection from beams’ eye view are used as supervised parameters to determine the optimal isocenter numbers. The collimator angle is optimized by minimizing the sum of the MLC opening area from all gantry angles for each arc. In all, 10 clinical cases treated during 2016–2017 were compared to plan quality of GO script generated plans. Paddick gradient index (GI), conformity index (CI), and local brain volume receiving 12 Gy (local V12 Gy) around each lesion were compared. Result For four cases, the number of isocenters was reduced in the GO plans. For four other cases, the GO plans had the same number of isocenters as their corresponding clinical plans but with different lesion grouping. The GO plans had significantly lower GI (4.1 ± 1.0 vs 4.4 ± 0.9, P

OBJECTIVE Stereotactic biopsy is increasingly performed on brain metastases (BrMs) as improving cancer outcomes drive aggressive multimodality treatment, including laser interstitial thermal therapy (LITT). However, the tract recurrence (TR) risk is poorly defined in an era defined by focused-irradiation paradigms. As such, the authors aimed to define indications and adjuvant therapies for this procedure and evaluate the BrM-biopsy TR rate. METHODS In a single-center retrospective review, the authors identified stereotactic BrM biopsies performed from 2002 to 2020. Surgical indications, radiographic characteristics, stereotactic planning, dosimetry, pre- and postoperative CNS-directed and systemic treatments, and clinical courses were collected. Recurrence was evaluated using RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) criteria. RESULTS In total, 499 patients underwent stereotactic intracranial biopsy for any diagnosis, of whom 25 patients (5.0%) underwent biopsy for pathologically confirmed viable BrM, a proportion that increased over the time period studied. Twelve of the 25 BrM patients had ≥ 3 months of radiographic follow-up, of whom 6 patients (50%) developed new metastatic growth along the tract at a median of 5.0 months post-biopsy (range 2.3–17.1 months). All of the TR cases had undergone pre- or early post-biopsy stereotactic radiosurgery (SRS), and 3 had also undergone LITT at the time of initial biopsy. TRs were treated with resection, reirradiation, or observation/systemic therapy. CONCLUSIONS In this study the authors identified a nontrivial, higher than previously described rate of BrM-biopsy tract recurrence, which often required additional surgery or radiation and justified close radiographic surveillance. As BrMs are commonly treated with SRS limited to enhancing tumor margins, consideration should be made, in cases lacking CNS-active systemic treatments, to include biopsy tracts in adjuvant radiation plans where feasible.

An increasing number of patients with multiple brain metastases are being treated with stereotactic radiosurgery (SRS). Manually identifying and contouring all metastatic lesions is difficult and time-consuming, and a potential source of variability. Hence, we developed a 3D deep learning approach for segmenting brain metastases on MR and CT images. Five-hundred eleven patients treated with SRS were retrospectively identified for this study. Prior to radiotherapy, the patients were imaged with 3D T1 spoiled-gradient MR post-Gd (T1 + C) and contrast-enhanced CT (CECT), which were co-registered by a treatment planner. The gross tumor volume contours, authored by the attending radiation oncologist, were taken as the ground truth. There were 3 ± 4 metastases per patient, with volume up to 57 ml. We produced a multi-stage model that automatically performs brain extraction, followed by detection and segmentation of brain metastases using co-registered T1 + C and CECT. Augmented data from 80% of these patients were used to train modified 3D V-Net convolutional neural networks for this task. We combined a normalized boundary loss function with soft Dice loss to improve the model optimization, and employed gradient accumulation to stabilize the training. The average Dice similarity coefficient (DSC) for brain extraction was 0.975 ± 0.002 (95% CI). The detection sensitivity per metastasis was 90% (329/367), with moderate dependence on metastasis size. Averaged across 102 test patients, our approach had metastasis detection sensitivity 95 ± 3%, 2.4 ± 0.5 false positives, DSC of 0.76 ± 0.03, and 95th-percentile Hausdorff distance of 2.5 ± 0.3 mm (95% CIs). The volumes of automatic and manual segmentations were strongly correlated for metastases of volume up to 20 ml (r=0.97,p

Purpose Multibeam intensity modulated radiation therapy (IMRT) enhances the therapeutic index by increasing the dosimetric coverage of the targeted tumor tissues while minimizing volumes of adjacent organs receiving high doses of RT. The tradeoff is that a greater volume of lung is exposed to low doses of RT, raising concern about the risk of radiation pneumonitis (RP). Methods and Materials Between July 2010 and January 2013, patients with node-positive breast cancer received inverse-planned, multibeam IMRT to the breast or chest wall and regional nodes, including the internal mammary nodes (IMNs). The primary endpoint was feasibility, predefined by dosimetric treatment planning criteria. Secondary endpoints included the incidence of RP grade 3 or greater and changes in pulmonary function measured with the Common Terminology Criteria for Adverse Events version 3.0 scales, pulmonary function tests and community-acquired pneumonia questionnaires, obtained at baseline and 6 months after IMRT. Clinical follow-up was every 6 months for up to 5 years. Results Median follow-up was 53.4 months (range, 0-82 months). Of 113 patients enrolled, 104 completed follow-up procedures. Coverage of the breast or chest wall and IMN was comprehensive (median 48.1 Gy and 48.9 Gy, respectively). The median volume of lung receiving a high dose (V20Gy) and a low dose (V5) was 29% and 100%, respectively. The overall rate of respiratory toxicities was 10.6% (11/104), including 1 grade 3 RP event (0.96%). No differences were found in pulmonary function test or community-acquired pneumonia scores after IMRT. The 5-year rates of locoregional recurrence-free, disease-free, and overall survival were 93.2%, 63.6%, and 80.3%, respectively. Conclusions Multibeam IMRT in patients with breast cancer receiving regional nodal irradiation was dosimetrically feasible, based on early treatment planning criteria. Despite the large volume of lung receiving low-dose RT, the incidence of grade 3 RP was remarkably low, justifying inverse-planned IMRT as a treatment modality for patients with high-risk breast cancer in whom conventional RT techniques prove inadequate.

BackgroundAdjuvant stereotactic radiosurgery (SRS) improves the local control of resected brain metastases (BrM). However, the dependency of long-term outcomes on SRS timing relative to surgery remains unclear.MethodsRetrospective analysis of patients treated with metastasectomy-plus-adjuvant SRS at Memorial Sloan Kettering Cancer Center (MSK) between 2013 and 2016 was conducted. Kaplan-Meier methodology was used to describe overall survival (OS) and cumulative incidence rates were estimated by type of recurrence, accounting for death as a competing event. Recursive partitioning analysis (RPA) and competing risks regression modeling assessed prognostic variables and associated events of interest.ResultsTwo hundred and eighty-two patients with BrM had a median OS of 1.5 years (95% CI: 1.2-2.1) from adjuvant SRS with median follow-up of 49.8 months for survivors. Local surgical recurrence, other simultaneously SRS-irradiated site recurrence, and distant central nervous system (CNS) progression rates were 14.3% (95% CI: 10.1-18.5), 4.9% (95% CI: 2.3-7.5), and 47.5% (95% CI: 41.4-53.6) at 5 years, respectively. Median time-to-adjuvant SRS (TT-SRS) was 34 days (IQR: 27-39). TT-SRS was significantly associated with surgical site recurrence rate (P = 0.0008). SRS delivered within 1 month resulted in surgical site recurrence rate of 6.1% (95% CI: 1.3-10.9) at 1-year, compared to 9.2% (95% CI: 4.9-13.6) if delivered between 1 and 2 months, or 27.3% (95% CI: 0.0-55.5) if delivered >2 months after surgery. OS was significantly lower for patients with TT-SRS >~2 months. Postoperative length of stay, discharge to a rehabilitation facility, urgent care visits, and/or disease recurrence between surgery and adjuvant SRS associated with increased TT-SRS.ConclusionsAdjuvant SRS provides durable local control. However, delays in initiation of postoperative SRS can decrease its efficacy.

PURPOSE/OBJECTIVE(S) To evaluate the cumulative dose to organs at risk (OAR) for Glioblastoma multiforme (GBM) patients with multiple treatment courses via a purpose-developed RAdiotherapy Dose Accumulation Routine (RADAR), and to compare the results with manual estimations from the special medical physics consult (SPC). MATERIALS/METHODS RADAR as a treatment planning system plugin was created to automatically transfer dose from previous radiation treatment plans to the current planning CT based on approved rigid (RR) or deformable image registration (DIR), convert the physical dose in each voxel to equivalent dose in 2Gy fractions (EQD2), and subsequently accumulate EQD2 doses from all relevant treatments. RADAR provides a novel option to take the registration and contour uncertainty into considerations by conservatively replacing dose to a given OAR voxel with a local maximum dose searched within an ellipsoid of the voxel. Ten GBM cases treated with 2 or more radiation courses between 2017 to 2020 were selected to analyze the registration/contour uncertainties and compare OAR dose from SPC and RADAR retrospectively. Brainstem, optic chiasm, and both optic nerves on previous treatment scans were propagated to the current CT scan based on RR and DIR. For each structure, mean distance to agreement (MDA) was measured between propagated previous and current OAR contours, and used for assigning search radius of ellipsoids accounting for uncertainties. An α/β of 2 for OARs and 10 for gross tumor volume were used for EQD2 conversion. The maximum dose (Dmax) and dose to 5% volumes (D05) from the accumulated EQD2 dose was evaluated based on the structures in the most recent plan and compared to SPC estimated dose. The SPC dose was documented by adding dose reported to the OAR based on the structure set in each of the previous plans without considering dose location. RESULTS The mean, standard deviation of the MDA of brainstem, optic chiasm, left and right optic nerve were used to determine a search radius of 2.0 mm, 2.5 mm, 2.5 mm, and 2.5 mm for these OAR, respectively. Comparing the manually estimated EQD2 dose from SPC and RADAR, the dose differences of -23Gy up to 40 Gy were found. RADAR used current structure set for OAR evaluation whereas SPC used the structure set from each course. Inconsistencies in contouring can be attributed to the large dose difference for some cases. For 5 of 10 test cases, the RADAR-derived OARs dose was higher than departmental guidelines and would potentially trigger a re-plan. CONCLUSION RADAR is capable to automatically convert the physical dose to EQD2 dose with various treatment courses by rigid or deformable image registration, take into account the registration and contour uncertainties and evaluate accumulated dose more accurately and efficiently than manual estimation. RADAR improves the workflow of decision making when optimizing plans with multiple previous treatments.

Purpose This study aimed to evaluate and compare different system calibration methods from a large cohort of systems to establish a commissioning procedure for surface‐guided frameless cranial stereotactic radiosurgery (SRS) with intrafractional motion monitoring and gating. Using optical surface imaging (OSI) to guide non‐coplanar SRS treatments, the determination of OSI couch‐angle dependency, baseline drift, and gated‐delivered‐dose equivalency are essential. Methods Eleven trained physicists evaluated 17 OSI systems at nine clinical centers within our institution. Three calibration methods were examined, including 1‐level (2D), 2‐level plate (3D) calibration for both surface image reconstruction and isocenter determination, and cube phantom calibration to assess OSI‐megavoltage (MV) isocenter concordance. After each calibration, a couch‐angle dependency error was measured as the maximum registration error within the couch rotation range. A head phantom was immobilized on the treatment couch and the isocenter was set in the middle of the brain, marked with the room lasers. An on‐site reference image was acquired at couch zero, the facial region of interest (ROI) was defined, and static verification images were captured every 10° for 0°–90° and 360°–270°. The baseline drift was assessed with real‐time monitoring of the motionless phantom over 20 min. The gated‐delivered‐dose equivalency was assessed using the electron portal imaging device and gamma test (1%/1mm) in reference to non‐gated delivery. Results The maximum couch‐angle dependency error occurs in longitudinal and lateral directions and is reduced significantly (P 98% gamma‐test passing rate. Conclusion A commissioning method is recommended using the 3D plate calibration, which is verified by radiation isocenter and validated with couch‐angle dependency, baseline drift, and gated‐delivered‐dose equivalency tests. This method characterizes OSI uncertainties, ensuring motion‐monitoring accuracy for SRS treatments.

Purpose To evaluate two three‐dimensional (3D)/3D registration platforms, one two‐dimensional (2D)/3D registration method, and one 3D surface registration method (3DS). These three technologies are available to perform six‐dimensional (6D) registrations for image‐guided radiotherapy treatment. Methods Fiducial markers were asymmetrically placed on the surfaces of an anthropomorphic head phantom (n = 13) and a body phantom (n = 8), respectively. The point match (PM) solution to the six‐dimensional (6D) transformation between the two image sets [planning computed tomography (CT) and cone beam CT (CBCT)] was determined through least‐square fitting of the fiducial positions using singular value decomposition (SVD). The transformation result from SVD was verified and was used as the gold standard to evaluate the 6D accuracy of 3D/3D registration in Varian’s platform (3D3DV), 3D/3D and 2D/3D registration in the BrainLab ExacTrac system (3D3DE and 2D3D), as well as 3DS in the AlignRT system. Image registration accuracy from each method was quantitatively evaluated by root mean square of target registration error (rmsTRE) on fiducial markers and by isocenter registration error (IRE). The Wilcoxon signed‐rank test was utilized to compare the difference of each registration method with PM. A P

This chapter describes recent advancements in image guidance and optical surface mapping that have made frameless cranial radiosurgery feasible. A clinical case is first briefly discussed to demonstrate the need to develop a flexible frameless radiosurgery technique, followed by a general background of cranial radiosurgery. The frameless radiosurgery technique is described, including the patient immobilization system, various image guidance systems with emphasis on optical surface imaging for real-time pre-setup patient alignment and on-treatment motion monitoring, and the need for staff training and credentialing. The accuracies of these systems are discussed to demonstrate that the frameless radiosurgery can achieve adequate spatial accuracy with improved patient comfort, enhanced capability, and additional clinical flexibility. Finally, some clinical recommendations and future directions are provided based on our clinical experience with image-guided frameless radiosurgery.

Background and Purpose This study summarizes the cranial stereotactic radiosurgery (SRS) volumetric modulated arc therapy (VMAT) procedure at our institution. Materials and Methods Volumetric modulated arc therapy plans were generated for 40 patients with 188 lesions (range 2–8, median 5) in Eclipse and treated on a TrueBeam STx. Limitations of the custom beam model outside the central 2.5 mm leaves necessitated more than one isocenter pending the spatial distribution of lesions. Two to nine arcs were used per isocenter. Conformity index (CI), gradient index (GI) and target dose heterogeneity index (HI) were determined for each lesion. Dose to critical structures and treatment times are reported. Results Lesion size ranged 0.05–17.74 cm3 (median 0.77 cm3), and total tumor volume per case ranged 1.09–26.95 cm3 (median 7.11 cm3). For each lesion, HI ranged 1.2–1.5 (median 1.3), CI ranged 1.0–2.9 (median 1.2), and GI ranged 2.5–8.4 (median 4.4). By correlating GI to PTV volume a predicted GI = 4/PTV0.2 was determined and implemented in a script in Eclipse and used for plan evaluation. Brain volume receiving 7 Gy (V 7 Gy) ranged 10–136 cm3 (median 42 cm3). Total treatment time ranged 24–138 min (median 61 min). Conclusions Volumetric modulated arc therapy provide plans with steep dose gradients around the targets and low dose to critical structures, and VMAT treatment is delivered in a shorter time than conventional methods using one isocenter per lesion. To further improve VMAT planning for multiple cranial metastases, better tools to shorten planning time are needed. The most significant improvement would come from better dose modeling in Eclipse, possibly by allowing for customizing the dynamic leaf gap (DLG) for a special SRS model and not limit to one DLG per energy per treatment machine and thereby remove the limitation on the Y‐jaw and allow planning with a single isocenter.

PurposeToestablish the maximum tolerated dose of a 3-fraction hypofractionated stereotactic reirradiation schedule when delivered with concomitant bevacizumab to treat recurrent high-grade gliomas.Methods and materialsPatients with recurrent high-grade glioma with Karnofsky performance status ≥60, history of standard fractionated initial radiation, tumor volume at recurrence ≤40cm3, and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 phase 1 dose escalation trial design was utilized, with dose-limiting toxicities defined as any grade 3 to 5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10mg/kg every 2weeks. Hypofractionated stereotactic reirradiation was initiated after 2 bevacizumab doses, delivered in 3 fractions every other day, starting at 9Gy per fraction.ResultsA total of 3 patients were enrolled at the 9Gy×3 dose level cohort, 5 in the 10Gy×3 cohort, and 7 in the 11Gy×3 cohort. One dose-limiting toxicity of grade 3 fatigue and cognitive deterioration possibly related to hypofractionated stereotactic reirradiation was observed in the 11Gy×3 cohort, and this dose was declared the maximum tolerated dose in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival was 13months.ConclusionsReirradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11Gy×3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison with our previous 6 Gy×5 schedule. Promising overall survival warrants further investigation.

Background and purpose Hypofractionated conformal radiotherapy (hfCRT) is used for larger brain metastases or metastases near critical structures. We investigated hfCRT outcomes for newly diagnosed brain metastases. Materials and methods We identified 195 patients with 1–3 brain metastases who underwent 5×6Gy hfCRT for 231 lesions from 2007 to 2013. Associations among clinical factors, local control (LC), distant brain control (DC) and overall survival (OS) were tested using univariate and multivariate (MVA) Cox regression analysis and Kaplan–Meier method. Results Median follow-up was 12.8months. One hundred forty-three (62%) lesions were treated with hfCRT post-operatively, and 88 (38%) with definitive hfCRT. LC for all lesions was 83% at 1year. For lesions treated with post-operative hfCRT, tumor size (HR=4.7, p =0.04) and subtotal resection (HR=2.7, p =0.02) were predictive of local failure on MVA. For lesions ≥2.8cm in size, LC was 61% at 12months for lesions status-post subtotal resection, compared to 84% status-post gross total resection ( p =0.004). Extracranial disease presence was associated with worse DC (HR=1.8, p =0.008) and OS (HR=3.1, p Conclusions We showed 5×6Gy hfCRT provides acceptable LC at 1year for limited brain metastases. For large lesions not grossly resected, more aggressive strategies can be considered to improve LC.

Spine stereotactic body radiation therapy frequently involves the delivery of high doses to targets in proximity to the spinal cord; thus, the radiation must be delivered with great spatial accuracy. Monitoring for large shifts in target and cord position that might occur during dose delivery is a challenge for clinics equipped with a conventional C-arm Linac. Treatment must be halted, then imaging and registration must be done to determine whether a significant shift has occurred. In this retrospective study of 1019 spine SBRT treatments, we investigated the number of target shifts >2 mm in any direction that occurred in carefully immobilized patients. Orthogonal kV images were acquired 3 to 5 times during each session using in an in-room imaging system. Although the likelihood of large intrafractional shifts was found to be very low, they did occur in 6 treatment sessions. Intrafractional monitoring was found to be an important safety component of treatment delivery.

Locally advanced breast cancer patients with expander or implant reconstructions who require comprehensive postmastectomy radiotherapy (PMRT) can pose unique treatment planning challenges. Traditional 3D conformal radiation techniques often result in large dose inhomogeneity throughout the treatment volumes, inadequate target coverage, or excessive normal tissue doses. We have developed a volumetric modulated arc therapy (VMAT) planning technique without entering through the ipsilateral arm that produced adequate target volume coverage, excellent homogeneity throughout the target volume, and acceptable doses to the normal structures. Twenty left-sided and 10 right-sided patients with either ipsilateral or bilateral permanent implants or tissue expanders who received comprehensive PMRT between October 2014 and February 2016 were included in this study. Ten left-sided cases used deep inspiration breath hold (DIBH) technique, and others used free breathing (FB). Planning target volume (PTV) included chestwall, internal mammary nodes (IMNs), supraclavicular, and axillary lymph nodes. A VMAT plan using 4 or 5 partial arcs with 6 MV photon beam avoiding entering through the ipsilateral arm was generated for each patient. Prescription dose was 50 Gy in 25 fractions. PTV coverage, maximum depth of IMNs, dose homogeneity and dose to the heart, lungs, thyroid, contralateral intact breast or implant, liver, stomach, left anterior descending artery, ipsilateral brachial plexus, esophagus, spinal cord, and total MU were evaluated. PTV D95% (Gy) was 49.6 ± 0.9, 48.7 ± 0.9, and 49.5 ± 1.1; PTV D05% (Gy) was 55.7 ± 0.6, 55.1 ± 1.4, and 55.0 ± 0.7; maximum depth of IMNs (cm) was 4.3 ± 0.9, 4.6 ± 1.1, and 4.9 ± 2.3; ipsilateral lung, V20Gy (%) was 29.0 ± 2.1, 28.8 ± 2.5, and 27.5 ± 3.4; heart mean dose (Gy) was 4.2 ± 0.4, 7.5 ± 1.1, and 6.6 ± 0.8 for right-sided FB, left-sided FB, and left-sided DIBH cases, respectively. D95% of IMNs all received 100% prescription dose. The maximum dose (Gy) to the left anterior descending artery was 33.8 ± 11.7 for left-sided FB and 31.4 ± 7.3 for left-sided DIBH. VMAT technique avoiding ipsilateral arm can produce acceptable clinical plans for locally advanced breast cancer patients with expander or implant reconstructions receiving comprehensive PMRT.

Background Brain metastases are common in patients with metastatic melanoma. With increasing numbers of melanoma patients on anti-PD-1 therapy, we sought to evaluate the safety and initial response of brain metastases treated with concurrent pembrolizumab and radiation therapy. Methods From an institutional database, we retrospectively identified patients with melanoma brain metastases treated with radiation therapy (RT) who received concurrent pembrolizumab. Concurrent treatment was defined as RT during pembrolizumab administration period and up to 4 months after most recent pembrolizumab treatment. Response was categorized by change in maximum diameter on first scheduled follow-up MRI. Lesion and patient specific outcomes including response, lesion control, brain control and overall survival were recorded and descriptively compared to contemporary treatments with RT and concurrent ipilimumab or RT without immunotherapy. Results From January 2014 through December 2015, we identified 21 patients who received concurrent radiation therapy and pembrolizumab for brain metastases or resection cavities that had at least one scheduled follow-up MRI. Eleven underwent stereotactic radiosurgery (SRS), 7 received hypofractionated radiation and 3 had whole brain treatment (WBRT). All treatments were well tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion occurred in 1 patient treated with WBRT after prior SRS. For metastases treated with SRS, at first scheduled follow-up MRI (median 57 days post SRS), 70% (16/23) exhibited complete (CR, n = 8) or partial response (PR, n = 8). The intracranial response rates (CR/PR) for patients treated with SRS and concurrent ipilimumab and SRS without concurrent immunotherapy was 32% and 22%, respectively. Conclusions Concurrent pembrolizumab with brain RT appears safe in patients with metastatic melanoma, and SRS in particular is effective in markedly reducing the size of brain metastases at the time of first follow-up MRI. These results compare favorably to SRS in combination with ipilimumab and SRS without concurrent immunotherapy.

Purpose: To develop a new method for accurate measurement of dynamic respiratory tidal volume, we investigate the feasibility of measuring torso volume change using optical surfaceimaging (OSI). Methods: Based on a validated volume conservation theory, the tidal volume is equal to the volume change of the torso during quiet respiration (Li et al, PMB, 54:1693, 2009). A clinical OSI system was employed to acquire surfaceimages of seven geometric phantoms and two ‘deformable’ torso phantoms. The mesh surfaceimages were converted into contours for volume calculation using a treatment planning system. For geometric phantoms, their volumes under the incomplete surfaceimages were calculated with aid of their symmetry. The results were compared with theoretical calculation and water containment experiments. For deformable torso phantoms, we created volume‐controlled deformation stages by placing deformable PlayDoh (DPD) materials on top of rigid Rando/Thorax phantoms, mimicking respiration‐induced torso surface elevation and volume change. The volume difference under the surfaces with and without the DPD padding was calculated with aid of a common posterior line to enclose the region of interest. Three different volumes of DPD padding (>500cc) were mounted on the torso phantoms and CT scanned for volume measurements. Results: For geometric phantoms, the OSI measured volume had accuracy (±1s) of 0.0%±1.6% (vs. geometric volume calculation) and 0.6%±3.8% (vs. water containment experiment). For deformable torso phantoms, the volume change was measured using OSI with an accuracy of 1.5%±2.5% against the measured volume using CTimaging.Linear regression showed a one‐to‐one relationship between the OSI volumes and CT volumes with a slope of 1.003 (r2=0.999). Conclusions: The optical surfaceimaging system can accurately measure the volume of geometric phantoms and the volume change of deformable torso phantoms. The accuracy is about 3% against standard volume measurement methods. Further study on human subjects is under investigation. Memorial Sloan‐Kettering Cancer Center has a reserach agreement with Vision RT, Inc.

PURPOSE: For left-sided postmastectomy patients requiring chest wall plus comprehensive nodal irradiation, sometimes traditional techniques such as partial wide tangents or electron/tangents combination are not feasible due to abnormal chest wall contour or heart position or unusually wide excision scar. We developed electron chest wall irradiation technique using Electron Monte Carlo (EMC) dose algorithm that will achieve heart sparing with acceptable ipsilateral lung dose, minimal contralateral lung and breast dose. METHODS: Ten left-sided postmastectomy patients with very challenging anatomy were selected for this dosimetry study. The enface electron fields were designed from a single isocenter and gantry angle with different energy beams using different cutouts that matched on the skin. Smaller energy was used in the central thin chest wall part and higher energy in the medial internal mammary nodes (IMN) area, superior part of the thick chest wall, and/or Axilla area. The electron fields were matched to the photon supra-clavicular field in the superior region. Daily field junctions were used to feather the match lines between all the fields. Electron field dose calculations were done with Monte Carlo. RESULTS: Five patients’ chest wall fields were planned with 6/9MeVcombination, one with 6/12 MeV, two 9/12MeV and one 9/16MeV, and one with 6/9/12MeV. Institutional criteria of prescription dose of 50Gy for target volumes and normal tissue dose were met with this technique in spite of the challenging anatomy. Mean heart dose averaged 3.0Gy ± 0.8Gy. For ipsilateral lung, V20Gy and V5Gy averaged 33.2% ± 4.5% and 64.6% ± 9.6% respectively. For contralateral lung, V5Gy averaged 5.1% ± 5.0%. For contralateral breast, V5Gy averaged 3.3% ± 3.1%. CONCLUSIONS: The electron chest wall irradiation technique using electron Monte Carlo dose algorithm can provide adequate dose coverage to the chest wall, IMNs and/or Axilla nodes while achieving heart sparing with acceptable ipsilateral lung dose, minimal contralateral lung and breast dose.

To provide a comprehensive assessment of patient setup accuracy in 6 degrees of freedom (DOFs) using 2-dimensional/3-dimensional (2D/3D) image registration with on-board 2-dimensional kilovoltage (OB-2DkV) radiographic images, we evaluated cranial, head and neck (HN), and thoracic and abdominal sites under clinical conditions. A fast 2D/3D image registration method using graphics processing unit GPU was modified for registration between OB-2DkV and 3D simulation computed tomography (simCT) images, with 3D/3D registration as the gold standard for 6DOF alignment. In 2D/3D registration, body roll rotation was obtained solely by matching orthogonal OB-2DkV images with a series of digitally reconstructed radiographs (DRRs) from simCT with a small rotational increment along the gantry rotation axis. The window/level adjustments for optimal visualization of the bone in OB-2DkV and DRRs were performed prior to registration. Ideal patient alignment at the isocenter was calculated and used as an initial registration position. In 3D/3D registration, cone-beam CT (CBCT) was aligned to simCT on bony structures using a bone density filter in 6DOF. Included in this retrospective study were 37 patients treated in 55 fractions with frameless stereotactic radiosurgery or stereotactic body radiotherapy for cranial and paraspinal cancer. A cranial phantom was used to serve as a control. In all cases, CBCT images were acquired for patient setup with subsequent OB-2DkV verification. It was found that the accuracy of the 2D/3D registration was 0.0 ± 0.5 mm and 0.1° ± 0.4° in phantom. In patient, it is site dependent due to deformation of the anatomy: 0.2 ± 1.6 mm and −0.4° ± 1.2° on average for each dimension for the cranial site, 0.7 ± 1.6 mm and 0.3° ± 1.3° for HN, 0.7 ± 2.0 mm and −0.7° ± 1.1° for the thorax, and 1.1 ± 2.6 mm and −0.5° ± 1.9° for the abdomen. Anatomical deformation and presence of soft tissue in 2D/3D registration affect the consistency with 3D/3D registration in 6DOF: the discrepancy increases in superior to inferior direction.

To evaluate local control after surgical resection and postoperative stereotactic radiosurgery (SRS) for brain metastases.A total of 49 patients (50 lesions) were enrolled and available for analysis. Eligibility criteria included histologically confirmed malignancy with 1 or 2 intraparenchymal brain metastases, age≥18 years, and Karnofsky performance status (KPS)≥70. A Cox proportional hazard regression model was used to test for significant associations between clinical factors and overall survival (OS). Competing risks regression models, as well as cumulative incidence functions, were fit using the method of Fine and Gray to assess the association between clinical factors and both local failure (LF; recurrence within surgical cavity or SRS target), and regional failure (RF; intracranial metastasis outside of treated volume).The median follow-up was 12.0 months (range, 1.0-94.1 months). After surgical resection, 39 patients with 40 lesions were treated a median of 31 days (range, 7-56 days) later with SRS to the surgical bed to a median dose of 1800 cGy (range, 1500-2200 cGy). Of the 50 lesions, 15 (30%) demonstrated LF after surgery. The cumulative LF and RF rates were 22% and 44% at 12 months. Patients who went on to receive SRS had a significantly lower incidence of LF (P=.008). Other factors associated with improved local control include non-small cell lung cancer histology (P=.048), tumor diameter3 cm (P=.010), and deep parenchymal tumors (P=.036). Large tumors (≥3 cm) with superficial dural/pial involvement showed the highest risk for LF (53.3% at 12 months). Large superficial lesions treated with SRS had a 54.5% LF. Infratentorial lesions were associated with a higher risk of developing RF compared to supratentorial lesions (P.001).Postoperative SRS is associated with high rates of local control, especially for deep brain metastases3 cm. Tumors≥3 cm with superficial dural/pial involvement demonstrate the highest risk of LF.

PURPOSE To establish a new clinical procedure in frameless stereotactic radiosurgery (SRS) for patient setup verification at treatment couch angles as well as for head-motion monitoring during treatment using video-based optical surface imaging (OSI). METHODS A video-based three-dimensional (3D) OSI system with three ceiling-mounted camera pods was employed to verify setup at treatment couch angles as well as to monitor head motion during treatment. A noninvasive head immobilization device was utilized, which includes an alpha head mold and a dental mouthpiece with vacuum suction; both were locked to the treatment couch. Cone beam computed tomography (CBCT) was used as the standard for image-guided setup. Orthogonal 2D-kV imaging was applied for setup verification before treatment, between couch rotations, and after treatment at zero couch angle. At various treatment couch angles, OSI setup verification was performed, relative to initial OSI setup verification at zero couch angle after CBCT setup through a coordinate transformation. For motion monitoring, the setup uncertainty was decoupled by taking an on-site surface image as new reference to detect motion-induced misalignment in near real-time (1-2 frames per second). Initial thermal instability baseline of the real-time monitoring was corrected. An anthropomorphous head phantom and a 1D positioning platform were used to assess the OSI accuracy in motion detection in longitudinal and lateral directions. Two hypofractionated (9 Gy x 3 and 6 Gy x 5) frameless stereotactic radiotherapy (SRT) patients as well as two single-fraction (21 and 18 Gy) frameless SRS patients were treated using this frameless procedure. For comparison, 11 conventional frame-based SRS patients were monitored using the OSI to serve as clinical standards. Multiple noncoplanar conformal beams were used for planning both frameless and frame-based SRS with a micromultileaf collimator. RESULTS The accuracy of the OSI in 1D motion detection was found to be 0.1 mm with uncertainty of +/- 0.1 mm using the head phantom. The OSI registration against simulation computed tomography (CT) external contour was found to be dependent on the CT skin definition with -0.4 mm variation. For frame-based SRS patients, head-motion magnitude was detected to be

Purpose The purpose of this study was to investigate how incorporation of magnetic resonance spectroscopy imaging (MRSI) into radiotherapy planning would increase the target volume for patients with recurrent glioma. Methods After prior standard radiotherapy, 25 patients with recurrent glioma were treated with bevacizumab and concurrent hypofractionated stereotactic radiotherapy (HFSRT), delivering 30 Gy in five fractions. MRSI were acquired for 12 patients. Areas with markedly higher choline levels relative to the levels of total creatine and N-acetylaspartate were identified and referred to as MRSI voxels with elevated metabolite ratios (EMR). Gross tumor volume (GTV) consisted of contrast-enhancing tumor on T1-weighted magnetic resonance images (MRI) and computed tomography. Clinical target volume (CTV) was GTV + 5 mm margin and MRSI voxels with EMR. Overall survival (OS) and 6-month progression free survival (PFS) for these patients were reported in a prior publication [Gutin et al., Int. J. Radiat. Oncol., Biol., Phys. 75(1), 156-163 (2009)], and the outcome was correlated with the GTV and the volume of MRSI voxels with EMR in this study. Results Seven of the 12 patients had MRSI voxels with EMR. If none of the MRSI voxels with EMR were included, the CTV would range from 9.2 to 73.0 cm3 with a median of 31.0 cm3, whereas if all voxels were included, the CTV would range from 27.4 to 74.4 cm3 with a median of 35.0 cm3. For three of the seven patients, including the voxels with EMR, would have increased the CTV by 14%-23%. For one patient, where the MRSI voxels with EMR did not overlap the GTV, including these voxels would increase the CTV by 198%. No correlation could be found between the OS and PFS and the GTV or the volume of MRSI voxels with EMR. Conclusions Seven of 12 patients with recurrent glioma had MRSI voxels with EMR. For four of these seven patients, including the MRSI voxels with EMR, significantly increased the CTV. This study does not have statistical power to conclude on the importance of including areas with MRSI-suspect disease into the radiation target volume.

Background/purpose To evaluate radiation plans of patients undergoing mastectomy with immediate expander-implant reconstruction followed by postmastectomy radiation therapy (PMRT). Materials/methods We identified 41 patients from June 2004 to May 2007 who underwent mastectomy, immediate expander-implant reconstruction, and PMRT with intensity-modulated radiation therapy. We assessed chest wall (CW) coverage and volume of heart and lung irradiated. Results In 73% of patients, all CW borders were adequately covered, and in 22%, all but 1 border were adequately covered. The total lung V 20 was V 20 was 13% (range, 3–23%), and the mean heart D mean was 2.81 Gy (range, 0.53–9.60 Gy). In patients with left-sided lesions without internal mammary nodes (IMNs) treatment ( n = 22), the mean lung V 20 was 12.6% and the mean heart D mean was 3.90 Gy, and in the patient with IMN treatment, the lung V 20 was 18% and heart D mean was 8.04 Gy. For right-sided lesions without IMN treatment ( n = 12), the mean lung V 20 was 12.4% and the mean heart D mean was 0.90 Gy, and in patients with IMN treatment ( n = 6), these numbers were 17.8% and 1.76 Gy. At a median follow-up of 29 months, the 30-month actuarial local control was 97%. Conclusions In women undergoing immediate expander-implant reconstruction, PMRT can achieve excellent local control with acceptable heart and lung doses. These results can be achieved even when the IMN are being treated, although doses to the heart and lungs will be higher.

Liposomes have been widely used delivery systems, particularly relevant to the development of cancer therapeutics. Numerous liposome-based drugs are in the clinic or in clinical trials today against multiple tumor types; however, systematic studies of liposome interactions with solid or metastatic tumor nodules are scarce. This study is describing the in vitro interaction between liposomes and avascular human prostate (LNCaP-LN3) tumor spheroids. The ability of fluorescently labelled liposomal delivery systems of varying physicochemical characteristics to penetrate within multicellular tumor spheroids has been investigated by confocal laser scanning microscopy. A variety of liposome characteristics and experimental parameters were investigated, including lipid bilayer composition, duration of liposome-spheroid interaction, mean liposome size, steric stabilization of liposomes. Electrostatic binding between cationic liposomes and spheroids was very efficient; however, it impeded any significant penetration of the vesicles within deeper layers of the tumor spheroid. Small unilamellar liposomes of neutral surface character did not bind as efficiently but exhibited enhanced penetrative transport capabilities closer to the tumor core. Polymer-coated (sterically stabilised) liposomes exhibited almost no interaction with the spheroid, indicating that their limited diffusion within avascular tissues may be a limiting step for their use against micrometastases. Multicellular tumor spheroids were used as models of solid tumor interstitium relevant to delivery systems able to extravasate from the microcapillaries or as models of prevascularized micrometastases. This study illustrates that interactions between liposomes and other drug delivery systems with multicellular tumor spheroids can offer critically important information with respect to optimizing solid or micrometastatic tumor delivery and targeting strategies. J Liposome Res

Purpose: The humanized monoclonal antibody, trastuzumab (Herceptin), directed against HER2/neu, has been effective in the treatment of breast cancer malignancies. However, clinical activity has depended on HER2/neu expression. Radiolabeled trastuzumab has been considered previously as a potential agent for radioimmunotherapy. The objective of this study was to investigate the efficacy of trastuzumab labeled with the α-particle emitting atomic generator, actinium-225 (225Ac), against breast cancer spheroids with different HER2/neu expression levels. 225Ac has a 10-day half-life and a decay scheme yielding four α-particles. Experimental Design: The breast carcinoma cell lines MCF7, MDA-MB-361 (MDA), and BT-474 (BT) with relative HER2/neu expression (by flow cytometry) of 1:4:18 were used. Spheroids of these cell lines were incubated with different concentrations of 225Ac-trastuzumab, and spheroid growth was measured by light microscopy over a 50-day period. Results: The activity concentration required to yield a 50% reduction in spheroid volume at day 35 was 18.1, 1.9, and 0.6 kBq/ml (490, 52, 14 nCi/ml) for MCF7, MDA, and BT spheroids, respectively. MCF7 spheroids continued growing but with a 20–30 day growth delay at 18.5 kBq/ml. MDA spheroid growth was delayed by 30–40 days at 3.7 kBq/ml; at 18.5 kBq/ml, 12 of 12 spheroids disaggregated after 70, days and cells remaining from each spheroid failed to form colonies within 2 weeks of being transferred to adherent dishes. Eight of 10 BT spheroids failed to regrow at 1.85 kBq/ml. All of the BT spheroids at activity concentrations 3.7 kBq/ml failed to regrow and to form colonies. The radiosensitivity of these three lines as spheroids was evaluated as the activity concentration required to reduce the treated to untreated spheroid volume ratio to 0.37, denoted DVR37. An external beam radiosensitivity of 2 Gy was found for spheroids of all three of the cell lines. After α-particle irradiation a DVR37 of 1.5, 3.0, and 2.0 kBq/ml was determined for MCF7, MDA, and BT, respectively. Conclusion: These studies suggest that 225Ac-labeled trastuzumab may be a potent therapeutic agent against metastatic breast cancer cells exhibiting intermediate to high HER2/neu expression.

Purpose: Cranial SRS VMAT plans must have steep dose gradient around each target to reduce dose to normal brain. This study reports on the correlation between gradient index (GI=V50%/V100%), target size and target dose heterogeneity index (HI=PTV Dmax/prescription dose) for multi-lesion cranial SRS VMAT plans. Methods: VMAT plans for 10 cranial cases with 3 to 6 lesions (total 39 lesions) generated in Varian Eclipse V11.0.47 with a fine-tuned AAA beam model and 0.125 cm dose grid were analyzed. One or two iso centers were used depending on the spatial distribution of lesions. Two to nine coplanar and non-coplanar arcs were used per isocenter. Conformity index (CI= V100%/VPTV), HI, and GI were determined for each lesion. Dose to critical structures were recorded. Results: Lesion size ranged from 0.05–11.00 cm3. HI ranged from 1.2–1.4, CI ranged from 1.0–2.8 and GI from 3.1–8.4. Maximum dose to brainstem, chiasm, lenses, optic nerves and eyes ranged from 120–1946 cGy, 47–463 cGy, 9–121 cGy, 14–512 cGy, and 17–294 cGy, respectively. Brain minus PTV (Brain-PTV) V7Gy was in the range 1.1–6.5%, and Brain-PTV Dmean was in the range 94–324 cGy. Conclusion: This work shows that a GI 0.4cc. For smaller lesions, GI increases rapidly. GI is lower when HI is increased. Based on this study, recommend HI is 1.4, and recommended GI is for volumes 1.0cc GI

Unlike β particle–emitting isotopes, α emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the β-emitters 131I and 90Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of β-emitting constructs, the α-emitting isotope 213Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg 213Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the 213Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with β-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of 213Bi-HuM195, and it is the first proof-of-concept for systemic targeted α particle immunotherapy in humans.

Patients undergo CT simulation in the treatment position with both arms extended above their head using an Alpha Cradle or breast board immobilization; IV contrast is not necessary. In cases where the patient has an intact breast, wires are placed around the borders of the breast on the patient’s skin prior to scanning. Patients are scanned from the cricoid through 5 cm below the clinically marked inferior port edge. The entire lung must be included.

To determine if the presence of bilateral implants, in addition to other anatomic and treatment-related variables, affects coverage of the target volume and dose to the heart and lung in patients receiving postmastectomy radiation therapy (PMRT). A total of 197 consecutive women with breast cancer underwent mastectomy and immediate tissue expander (TE) placement, with or without exchange for a permanent implant (PI) before radiation therapy at our center. PMRT was delivered with 2 tangential beams + supraclavicular lymph node field (50Gy). Patients were grouped by implant number: 51% unilateral (100) and 49% bilateral (97). The planning target volume (PTV) (defined as implant + chest wall + nodes), heart, and ipsilateral lung were contoured and the following parameters were abstracted from dose-volume histogram (DVH) data: PTV D95% > 98%, Lung V20Gy > 30%, and Heart V25Gy > 5%. Univariate (UVA) and multivariate analyses (MVA) were performed to determine the association of variables with these parameters. The 2 groups were well balanced for implant type and volume, internal mammary node (IMN) treatment, and laterality. In the entire cohort, 90% had PTV D95% > 98%, indicating excellent coverage of the chest wall. Of the patients, 27% had high lung doses (V20Gy > 30%) and 16% had high heart doses (V25Gy > 5%). No significant factors were associated with suboptimal PTV coverage. On MVA, IMN treatment was found to be highly associated with high lung and heart doses (both p < 0.0001), but implant number was not (p = 0.54). In patients with bilateral implants, IMN treatment was the only predictor of dose to the contralateral implant (p = 0.001). In conclusion, bilateral implants do not compromise coverage of the target volume or increase lung and heart dose in patients receiving PMRT. The most important predictor of high lung and heart doses in patients with implant-based reconstruction, whether unilateral or bilateral, is treatment of the IMNs. Refinement of radiation techniques in reconstructed patients who require comprehensive nodal irradiation is warranted.

Purpose: To commission a custom 6MV-SRS-AAA Eclipse beam model for VMAT multiple lesions cranial SRS treatment on a Varian TrueBeam STx. Methods: Six clinical plans were created using a customized beam model with dosimetric-leaf-gap(DLG) optimized for clinical treatments. Each plan had 4–6 non-isocentric targets with size from 0.2 to 7.1cc. All fields were measured with EBT3 film in the coronal plane in a solid water phantom and with an AS1000 EPID using gantry rotation. In addition, an end-to-end test was performed with coronal and sagittal films in an anthropomorphic phantom verifying dosimetry and localization accuracy. Portal dose distributions were generated with a custom portal dosimetry algorithm(PDIP). Measured dose distributions were compared with calculations using average dose difference (DD), and gamma function, γ. Using a 1.25mm grid, the γ criteria, local DD ≤ 3% and 2mm distance-to-agreement, were applied in regions with dose 50% of maximum. Results: The respective DD and γ for all films were 94.2%. The portal dose γ scores for all the plans were >94.9%. However, local regions with underdose >10%, were observed when targets were treated with the 5mm leaves. The same plans re-optimized with two isocenters such that all lesions were under the 2.5mm leaves did not show this effect. The DD and localization error of the end-to-end test were within 3.4% and 1.0mm respectively. Conclusion: The custom AAA beam model is capable of calculating acceptable dosimetry for targets using only the 2.5 mm leaves. This restricts lesions to within ±4cm of isocenter. The observed underdose beneath the 5mm leaves is attributed to a limitation in Eclipse that uses a single DLG representing the DLG's of both 2.5mm and 5mm leaves. If lesions are >4cm from isocenter, a multiple isocenter technique should be considered to allow the use of only the 2.5mm leaves.

Purpose: The prevailing approach to frameless SRS (fSRS) small field dosimetry is Gafchromic film. Though providing continuous information, its intrinsic uncertainties in fabrication, response, scan, and calibration often make film dosimetry subject to different interpretations. In this study, we explored the feasibility of using EPID portal dosimetry as a viable alternative to film for small field dosimetry. Methods: Plans prescribed a dose of 21 Gy were created on a flat solid water phantom with Eclipse V11 and iPlan for small static square fields (1.0 to 3.0 cm). In addition, two clinical test plans were computed by employing iPlan on a CIRS Kesler head phantom for target dimensions of 1.2cm and 2.0cm. Corresponding portal dosimetry plans were computed using the Eclipse TPS and delivered on a Varian TrueBeam machine. EBT-XD film dosimetry was performed as a reference. The isocenter doses were measured using EPID, OSLD, stereotactic diode, and CC01 ion chamber. Results: EPID doses at the center of the square field were higher than Eclipse TPS predicted portal doses, with the mean difference being 2.42±0.65%. Doses measured by EBT-XD film, OSLD, stereotactic diode, and CC01 ion chamber revealed smaller differences (except OSLDs), with mean differences being 0.36±3.11%, 4.12±4.13%, 1.7±2.76%, 1.45±2.37% for Eclipse and −1.36±0.85%, 2.38±4.2%, −0.03±0.50%, −0.27±0.78% for iPlan. The profiles measured by EPID and EBT-XD film resembled TPS (Eclipse and iPlan) predicted ones within 3.0%. For the two clinical test plans, the EPID mean doses at the center of field were 2.66±0.68% and 2.33±0.32% higher than TPS predicted doses. Conclusion: We found that results obtained with EPID portal dosimetry were slightly higher (∼2%) than those obtained with EBT-XD film, diode, and CC01 ion chamber with the exception of OSLDs, but well within IROC tolerance (5.0%). Therefore, EPID has the potential to become a viable real-time alternative method to film dosimetry.

Purpose: For left-sided PU patients requiring CW and nodal irradiation, sometimes partial wide tangents (PWT) are not feasible due to abnormal chest wall contour or heart position close to the anterior chest wall or unusual wide excision scar. We developed an energy modulated electron chest wall irradiation technique that will achieve heart sparing. Methods: Ten left-sided PU patients were selected for this dosimetry study. If PWT were used, the amount of the ipsilateral lung would be ranged 3.4 to 4.4 cm, and the amount of heart would be ranged 1.3 to 3.8 cm. We used electron paired fields that matched on the skin to achieve dose conformity to the chest wall. The enface electron fields were designed at extended SSD from a single isocenter and gantry angle with different energy beams using different cutout. Lower energy was used in the central chest wall part and higher energy was used in the periphery of the chest wall. Bolus was used for the electron fields to ensure adequate skin dose coverage. The electron fields were matched to the photon supra-clavicle field in the superior region. Daily field junctions were used to feather the match lines between all the fields. Target volumes and normal tissues were drawn according to institutional protocols. Prescription dose was 2Gy per fraction for a total 50Gy. Dose calculations were done with Eclipse EMC_11031 for Electron and AAA_11031 for photons. Results: Six patients were planned using 6/9MeV, three using 9/12MeV and one 6/12MeV. Target volumes achieved adequate coverage. For heart, V30Gy, V20Gy and Mean Dose were 0.6%±0.6%, 2.7%±1.7%, and 3.0Gy±0.8Gy respectively. For ipsilateral lung, V50Gy, V20Gy, V10Gy and V5Gy were 0.9%±1.1%, 34.3%±5.1%, 51.6%±6.3% and 64.1%±7.5% respectively. Conclusion: For left-sided PU patients with unusual anatomy, energy modulated electron CW irradiation technique can achieve heart sparing with acceptable lung dose.

To assess the impact of immediate breast reconstruction on postmastectomy radiation (PMRT) using dose-volume histogram (DVH) data.Two hundred forty-seven women underwent PMRT at our center, 196 with implant reconstruction and 51 without reconstruction. Patients with reconstruction were treated with tangential photons, and patients without reconstruction were treated with en-face electron fields and customized bolus. Twenty percent of patients received internal mammary node (IMN) treatment. The DVH data were compared between groups. Ipsilateral lung parameters included V20 (% volume receiving 20 Gy), V40 (% volume receiving 40 Gy), mean dose, and maximum dose. Heart parameters included V25 (% volume receiving 25 Gy), mean dose, and maximum dose. IMN coverage was assessed when applicable. Chest wall coverage was assessed in patients with reconstruction. Propensity-matched analysis adjusted for potential confounders of laterality and IMN treatment.Reconstruction was associated with lower lung V20, mean dose, and maximum dose compared with no reconstruction (all P.0001). These associations persisted on propensity-matched analysis (all P.0001). Heart doses were similar between groups (P=NS). Ninety percent of patients with reconstruction had excellent chest wall coverage (D9598%). IMN coverage was superior in patients with reconstruction (D9592.0 vs 75.7%, P.001). IMN treatment significantly increased lung and heart parameters in patients with reconstruction (all P.05) but minimally affected those without reconstruction (all P.05). Among IMN-treated patients, only lower lung V20 in those without reconstruction persisted (P=.022), and mean and maximum heart doses were higher than in patients without reconstruction (P=.006, P=.015, respectively).Implant reconstruction does not compromise the technical quality of PMRT when the IMNs are untreated. Treatment technique, not reconstruction, is the primary determinant of target coverage and normal tissue doses.

Purpose: Breast cancer patients with bilateral implant reconstructions who require postmastectomy radiotherapy can pose unique treatment planning challenges. The use of VMAT may provide advantages over conventional tangent or multi-beam IMRT techniques. Moreover, daily setup uncertainly of the arm position, however, could have significant impact on accurate dose delivery. This study compares the plan qualities between non-AA and AA VMAT techniques. Methods: Three breast cancer patients receiving left chest wall and regional nodal irradiation with bilateral implant reconstructions were studied. PTV included chest wall and IMNs (PTV-CW), and supraclavicular and axillary lymph nodes (PTV-SCV). For each patient, one non-AA VMAT plan (VMAT-S) with 4 partial arcs encompassing the ipsilateral arm and three AA VMAT plans where no arcs were entering or existing through the ipsilateral arm were generated. VMAT-AA1 uses 2 arcs for PTV-CW and 2 arcs for PTV-SCV. VMAT-AA2 used two static fields for PTV-SCV with 2 arcs for PTV-CW. VMAT-AA3 used 2 narrow arcs for PTV-CW and 2 long arcs for all PTVs. Prescription dose (PD) was 50 Gy (25 fractions). All plans were normalized to have 95% of PD to 95 % of PTV. PTV dose inhomogeneity and dose to the heart, left lung, right thyroid dose and left humerus were evaluated. Results: For VMAT-S, VMAT-AA1, VMAT-AA2 and VMAT-AA3, respectively, the average and standard deviation (in Gy unless specified otherwise) of PTV D05 are 54.7±0.9, 55.9±0.4, 56.7±0.7 and 55.7±0.4; mean Heart dose: 7.1±0.7, 7.2±0.8, 7.3±0.9 and 6.9±1.0; left lung V20Gy (in %): 28.1±1.0, 28.8+2.2, 32.2±4.1 and 27.8±2.0; mean right thyroid dose: 8.1±0.6, 5.1±2.1, 2.1±0.4 and 5.0±2.0; mean left humerus dose: 20.0±4.4,15.6±4.4, 15.2±8.2 and 15.3±4.6. Conclusion: AA VMAT can produce acceptable clinical plans while eliminating dosimetric impact related to arm setup uncertainty. These data require validation in larger planning studies prior to routine clinical implantation.

Purpose: As we continuously see more bilateral reconstructed chest wall cases, new challenges are being presented to deliver left-sided breast irradiation. We herein compare three Deep Inspiration Breath Hold (DIBH) planning techniques (tangents, VMAT, and IMRT) and two free breathing techniques (VMAT and IMRT). Methods: Three left-sided chest wall patients with bilateral implants were studied. Tangents, VMAT, and IMRT plans were created for DIBH scans. VMAT and IMRT plans were created for free breathing scans. All plans were normalized so that 95% of the prescription dose was delivered to 95% of the planning target volume (PTV). The maximum point dose was constrained to less than 120% of the prescription dose. Since the success of DIBH delivery largely depends on patient’s ability to perform consistent breath hold during beam on time, smaller number of Monitor Units (MU) is in general desired. For each patient, the following information was collected to compare the planning techniques: heart mean dose, left and right lung V20 Gy, contra-lateral (right) breast mean dose, cord max dose, and MU. Results: The average heart mean dose over all patients are 1561, 692, 985, 1245, and 1121 cGy, for DIBH tangents, VMAT, IMRT, free breathing VMAT and IMRT, respectively. For left lung V20 are 60%, 28%, 26%, 30%, and 29%. For contra-lateral breast mean dose are 244, 687, 616, 783, 438 cGy. MU are 253, 853, 2048, 1035, and 1874 MUs. Conclusion: In the setting of bilateral chest wall reconstruction, opposed tangent beams cannot consistently achieve desired heart and left lung sparing. DIBH consistently achieves better healthy tissue sparing. VMAT appears to be preferential to IMRT for planning and delivering radiation to patients with bilaterally reconstructed chest walls being treated with DIBH.

Purpose: Postmastectomy radiation therapy (PMRT) is often delivered to patients with permanent breast implants. On occasion, patients are irradiated with a tissue expander (TE) in place before their permanent implant exchange. Because of concern of potential under-dosing in these patients, we examined the dosimetric effects of the Magna-Site (Santa Barbara, CA) metallic port that is present in certain TEs. Methods and Materials: We performed ex vivo film dosimetry with single 6-MV and 15-MV photon beams on a water phantom containing a Magna-Site disc in two orientations. Additionally, using in vivo films, we measured the exit dose from 1 patient's TE-reconstructed breast during chest wall treatment with 15-MV tangent beams. Finally, we placed thermoluminescent dosimeters (TLDs) on 6 patients with TEs who received PMRT delivered with 15-MV tangent beams. Results: Phantom film dosimetry revealed decreased transmission in the region of the Magna-Site, particularly with the magnet in the parallel orientation (at 22 mm: 78% transmission with 6 MV, 84% transmission with 15 MV). The transmission measured by in vivo films during single beam treatment concurred with ex vivo results. TLD data showed acceptable variation in median dose to the skin (86–101% prescription dose). Conclusion: Because of potential dosimetric effects of the Magna-Site, it is preferable to treat PMRT patients with permanent implants. However, it is not unreasonable to treat with a TE because the volume of tissue affected by attenuation from the Magna-Site is small. In this scenario, we recommend using 15 MV photons with compensating bolus.

The liposomal delivery of cancer therapeutics, including gene therapy vectors, is an area of intense study. Poor penetration of liposomes into interstitial tumor spaces remains a problem, however. In this work, the penetration of different liposomal formulations into prostate carcinoma spheroids was examined. Spheroid penetration was assessed by confocal microscopy of fluorescently labeled liposomes. The impact of liposomal surface charge, mean diameter, lipid bilayer fluidity and fusogenicity on spheroid penetration was examined. A variety of different liposome systems relevant to clinical or preclinical protocols have been studied, including classical zwitterionic (DMPC:chol) and sterically stabilized liposomes (DMPC:chol:DOPE-PEG2000), both used clinically, and cationic liposomes (DMPC:DOPE:DC-chol and DOTAP), forming the basis of the vast majority of nonviral gene transfer vectors tested in various cancer trials. Surface interactions between strongly cationic vesicles and the tumor cells led to an electrostatically derived binding-site barrier effect, inhibiting further association of the delivery systems with the tumor spheroids (DMPC:DC-chol). However, inclusion of the fusogenic lipid DOPE and use of a cationic lipid of lower surface charge density (DOTAP instead of DC-chol) led to improvements in the observed intratumoral distribution characteristics. Sterically stabilized liposomes did not interact with the tumor spheroids, whereas small unilamellar classical liposomes exhibit extensive distribution deeper into the tumor volume. Engineering liposomal delivery systems with a relatively low charge molar ratio and enhanced fusogenicity, or electrostatically neutral liposomes with fluid bilayers, offered enhanced intratumoral penetration. This study shows that a delicate balance exists between the strong affinity of delivery systems for the tumor cells and the efficient penetration and distribution within the tumor mass, similar to previous work studying targeted delivery by ligand-receptor interactions of monoclonal antibodies. Structure-function relationships from the interaction of different liposome systems with 3-dimensional tumor spheroids can lead to construction of delivery systems able to target efficiently and penetrate deeper within the tumor interstitium and act as a screening tool for a variety of therapeutics against cancer. © 2004 Wiley-Liss, Inc.

Purpose: This study is designed to analyze the properties of beam path length at different brain locations and the effect of Inhomogeneity orrection (IC) on isocenter dose of cranial Stereotactic Radiosurgery(SRS)treatment planning.Method: Fifty five clinical cranial SRS plans, with total 63 lesions were analyzed in this study. Lesions were grouped as frontal (16 lesions), parietal (10 lesions), temporal (10 lesions), occipital (10 lesions), cerebellum (10 lesions), and acoustic neuroma (7 lesions). All plans were planned on Brainlab iPlan RT Dose 3.0.2. Pencil beam convolution dose calculation algorithm was used both with and without IC with identical beam parameters. Nine to 11 beams were used for each lesion. Average beam path length, and differences in isocenter dose for each lesion with and without IC were analyzed. Result: The mean and standard deviation (SD) of average beam path length for frontal, parietal, temporal, occipital, cerebellum and acoustic neuroma lesions without IC were 47.54±16.03mm, 45.33±8.69mm, 64.15±12.33mm, 51.27±9.73mm, 78.70±10.89mm and 79.92±7.46mm, respectively. The corresponding results with IC were 56.08±14.86mm, 52.80±8.79mm, 71.85±12.27mm, 59.97±10.20mm, 86.57±11.26mm and 90.07±7.57mm, respectively. The differences in average beam path length between with and without IC were 8.54±1.62mm, 7.47±1.04mm, 7.70±1.66mm, 8.71±1.56mm, 7.87±1.39mm and 10.15±3.52mm respectively. The mean and SD of isocenter dose for frontal, parietal, temporal, occipital, cerebellum, acoustic neuroma and all lesions combined without IC were 3.83±0.72%, 3.35±0.61%, 3.47±0.88%, 3.99±0.76%, 3.69±0.69%, 4.83 ±1.77% and 3.81±0.96% higher then the isocenter dose with IC, respectively. The maximum dose difference was 7.05% for an acoustic neuroma case and minimum dose difference was 1.59% for a frontal lobe lesion. Conclusion: In conclusion, an isodose difference between dose calculation with and without IC of about 4% was found for cranial SRS case. The effect of planning cranial SRS with or without IC increases with the average path length differences.

Purpose: To quantify the impact of kV cone beam CT (CBCT)‐guided setup on delivered dose to target and critical organs in patients receiving paraspinal irradiation and to compare the relative benefits of CBCT versus orthogonal kV radiograph (2D)‐guided setup. Method and Materials: Initial, pre‐ and post‐treatment CBCTs from ten patients receiving single‐fraction radiotherapy were evaluated. Delivered dose based on CBCT‐guided treatment was calculated after transferring target and critical organ contours from pre‐treatment CBCT to planning CT. Similarly, delivered dose from a simulated 2D setup was calculated by registering orthogonal DRRs created from the initial CBCT with planning DRRs using bony anatomy, and then applying the resulting shifts to the initial CBCT contours before transfer to the planning CT. The magnitude of residual setup errors and intra‐fractional motion were evaluated by registering pre‐treatment CBCT to planning CT and post‐ to pre‐treatment CBCT, respectively. Results:Dosimetric impact was evaluated using PTV D95% and maximum dose to critical structures. Even with CBCT‐guided setup, small residual setup errors combined with steep dose gradients led to increases up to 27% in maximum cord dose. Likewise, increases in esophagus maximum dose up to 34% (CBCT) and 20% (2D) were observed. PTV D95% decreased to 85% (CBCT) and 87% (2D) of planned dose for one patient with a low planned PTV D95% (73%) and a steep dose gradient. Magnitudes of the 3D vector of residual setup errors following 2D and CBCT setup were 2.3±0.5 mm and 1.5±0.4 mm, respectively. The intra‐fractional error was 1.6±0.3 mm. Conclusion: Since paraspinal lesions occur near stable bony anatomy with no significant anatomical deformation, CBCT provides no additional benefit over 2D techniques for accurate positioning. CBCT does provide easier visualization of the anatomy to facilitate setup and CBCT requires about the same effort as 2D setup based on orthogonal kV‐images.