Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study.

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

Patterns of utilization and clinical adoption of 0.35 Tesla MR-guided radiation therapy in the United States - Understanding the transition to adaptive, ultra-hypofractionated treatments.

Purpose/Objective: Magnetic resonance-guided radiation therapy (MRgRT) utilization is rapidly expanding worldwide, driven by advanced capabilities including continuous intrafraction visualization, automatic triggered beam delivery, and on-table adaptive replanning (oART). Our objective was to describe patterns of 0.35Tesla(T)-MRgRT (MRIdian) utilization in the United States (US) among early adopters of this novel technology. Materials/Methods: Anonymized administrative data from all US MRIdian treatment systems were extracted for patients completing treatment from 2014 to 2020. Detailed treatment information was available for all MRIdian linear accelerator (linac) systems and some cobalt systems. Results: Seventeen systems at 16 centers delivered 5736 courses and 36,389 fractions (fraction details unavailable for 1223 cobalt courses), of which 21.1% were adapted. Ultra-hypofractionation (UHfx) (1-5 fractions) was used in 70.3% of all courses. At least one adaptive fraction was used for 38.5% of courses (average 1.7 adapted fractions/course), with higher oART use in UHfx dose schedules (47.7% of courses, average 1.9 adapted fractions per course). The most commonly treated organ sites were pancreas (20.7%), liver (16.5%), prostate (12.5%), breast (11.5%), and lung (9.4%). Temporal trends show a compounded annual growth rate (CAGR) of 59.6% in treatment courses delivered, with a dramatic increase in use of UHfx to 84.9% of courses in 2020 and similar increase in use of oART to 51.0% of courses. Conclusions: This is the first comprehensive study reporting patterns of utilization among early adopters of MRIdian in the US. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of adaptive radiation therapy has led to a substantial transition to ultra-hypofractionated regimens. 0.35 T-MRgRT has been predominantly used to treat abdominal and pelvic tumors with increasing use of on-table adaptive replanning, which represents a paradigm shift in radiation therapy.

A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

Clinical adoption patterns of 0.35 Tesla MR-guided radiation therapy in Europe and Asia.

BACKGROUND: Magnetic resonance-guided radiotherapy (MRgRT) utilization is rapidly expanding, driven by advanced capabilities including better soft tissue imaging, continuous intrafraction target visualization, automatic triggered beam delivery, and the availability of on-table adaptive replanning. Our objective was to describe patterns of 0.35 Tesla (T)-MRgRT utilization in Europe and Asia among early adopters of this novel technology. METHODS: Anonymized administrative data from all 0.35T-MRgRT treatment systems in Europe and Asia were extracted for patients who completed treatment from 2015 to 2020. Detailed treatment information was analyzed for all MR-linear accelerators (linac) and -cobalt systems. RESULTS: From 2015 through the end of 2020, there were 5796 completed treatment courses delivered in 46,389 individual fractions. 23.5% of fractions were adapted. Ultra-hypofractionated (UHfx) dose schedules (1-5 fractions) were delivered for 63.5% of courses, with 57.8% of UHfx fractions adapted on-table. The most commonly treated tumor types were prostate (23.5%), liver (14.5%), lung (12.3%), pancreas (11.2%), and breast (8.0%), with increasing compound annual growth rates (CAGRs) in numbers of courses from 2015 through 2020 (pancreas: 157.1%; prostate: 120.9%; lung: 136.0%; liver: 134.2%). CONCLUSIONS: This is the first comprehensive study reporting patterns of utilization among early adopters of a 0.35T-MRgRT system in Europe and Asia. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of on-table adaptive RT have accelerated a transition to UHfx regimens. MRgRT has been predominantly used to treat tumors in the upper abdomen, pelvis and lungs, and increasingly with adaptive replanning, which is a radical departure from legacy radiotherapy practices.

Strategies of assessing and quantifying radiation treatment metabolic tumor response using F18 FDG Positron Emission Tomography (PET).

The use of positron emission tomography (PET) using F18 labeled fluorodeoxyglucose (FDG) for both oncology disease staging and radiation therapy target volume delineation has steadily increased over the last decade, and FDG-PET is today readily available in all major medical centers. The goal of anti tumor treatment, including chemotherapy and/or radiation therapy is to diminish a tumor cell population, ideally to the state of total eradication. Reducing the number of viable tumor cells can lead to a reduction in anatomical tumor size, and may also be correlated with decreased FDG uptake. Efforts to assess tumor response to therapy have attempted to describe and quantify changes in glucose utilization, also referred to as metabolic tumor response. In this review, an attempt is made to present and discuss methodologies to assess and quantify tumor metabolic response to radiation therapy or chemoradiation treatment courses.

Effect of body mass index on shifts in ultrasound-based image-guided intensity-modulated radiation therapy for abdominal malignancies.

BACKGROUND AND PURPOSE: We investigated whether corrective shifts determined by daily ultrasound-based image-guidance correlate with body mass index (BMI) of patients treated with image-guided intensity-modulated radiation therapy (IG-IMRT) for abdominal malignancies. The utility of daily image-guidance, particularly for patients with BMI>25.0, is examined. MATERIALS AND METHODS: Total 3162 ultrasound-directed shifts were performed in 86 patients. Direction and magnitude of shifts were correlated with pretreatment BMI. Bivariate statistical analysis and analysis of set-up correction data were performed using systematic and random error calculations. RESULTS: Total 2040 daily alignments were performed. Average 3D vector of set-up correction for all patients was 12.1mm/fraction. Directional and absolute shifts and 3D vector length were significantly different between BMI cohorts. 3D displacement averaged 4.9 mm/fraction and 6.8mm/fraction for BMI < or = 25.0 and BMI>25.0, respectively. Systematic error in all axes and 3D vector was significantly greater for BMI>25.0. Differences in random error were not statistically significant. CONCLUSIONS: Set-up corrections derived from daily ultrasound-based IG-IMRT of abdominal tumors correlated with BMI. Daily image-guidance may improve precision of IMRT delivery with benefits assessed for the entire population, particularly patients with increased habitus. Requisite PTV margins suggested in the absence of daily image-guidance are significantly greater in patients with BMI>25.0.

Evaluation of inter-fractional setup shifts for site-specific helical tomotherapy treatments.

This paper proposes to summarize and analyze the daily patient setup shifts based on megavoltage computed tomography (MVCT) image registration results for Helical TomoTherapy(R) (HT) treatment. One hundred and fifty-five consecutive treatment plans for a total of 137 patients delivered by the HT unit through one year were collected in this study. The patient data included pelvis (26%), abdomen (23%), lung (21%), head and neck (10%), prostate (8%), and others (12%). All the translational and roll rotational shifts made via auto MVCT and kilovoltage computed tomography (kVCT) image registration were recorded at each fraction. Manual fine-tuning was followed if automatic registration result was not satisfactory. The mean shift +/- one standard deviation (1 SD) was calculated for each patient based on the entire treatment course. For each treatment site, the average shift was analyzed as well as displacement in 3D vector. Statistical tests were performed to analyze the relationship of patient-specific, tumor site-specific, and fraction number association with the patient setup shifts. For all the treatment sites, the largest average shift was found in the anterior-posterior direction. The population standard deviations were between 1.2 and 5.6 mm for the X, Y, and Z directions and ranged from 0.2 to 0.6 degrees for the roll rotational correction. The largest standard deviations of the setup reproducibility in X, Y, and Z directions were found in lung patients (4.2 mm), abdomen, lung and spine patients (4.4 mm), and prostate patients (5.6 mm), respectively. The maximum 3D displacement was 10.9 mm for prostate patients' setup. ANOVA tests demonstrated the setup shifts were statistically different between patients even for those that were treated at the same tumor site in the translational directions. No strong correlation between the setup and the fraction number was found. In conclusion, the MVCT guided function in the HT treatment enables us to generate relatively accurate daily setup through registration with KVCT data sets. Our results indicate that lung, prostate, and abdominal patients are more prone to setup uncertainty and should be carefully evaluated.

Prospective evaluation of pretreatment executive cognitive impairment and depression in patients referred for radiotherapy.

PURPOSE: Cancer patients are at risk of cognitive impairment and depression. We sought to ascertain the prevalence of executive, visuospatial, memory, and general cognitive performance deficits before radiotherapy in a radiation oncology clinic referral population and correlate the neurocognitive measures with the depression symptom burden. METHODS AND MATERIALS: A total of 122 sequential patients referred for radiotherapy evaluation were administered a test battery composed of the Executive Interview (EXIT25), Executive Clock Drawing Task (CLOX1 and CLOX2), Mini Mental State Examination (MMSE), Memory Impairment Screen (MIS), and Geriatric Depression Scale (GDS). The mean age +/- standard deviation was 58 +/- 17 years. Of 122 patients, 24 (20%) had been referred for breast cancer, 21 (17%) for gastrointestinal cancer, 17 (14%) for genitourinary disease, and 8 (7%) for brain lesions; the rest were a variety of tumor sites. The cognitive performance among the tumor cohorts was compared using Bonferroni-corrected analysis of variance and Tukey-Kramer tests. Pearson correlation coefficients were determined between each cognitive instrument and the GDS. RESULTS: Of the 122 patients, 52 (43%) exhibited a detectable executive cognition decrement on one or more test measures. Five percent had poor memory performance (MIS), 18% had poor visuospatial performance (CLOX2), and 13% had poor global cognition (MMSE). Patients with brain tumors performed substantially worse on the EXIT25. No between-group differences were found for CLOX1, CLOX2, MIS, or GDS performance. The EXIT25 scores correlated significantly with the GDS scores (r = 0.26, p = 0.005). CONCLUSIONS: The results of this study have shown that patients referred for radiotherapy exhibit cognitive impairment profiles comparable to those observed in acutely ill medical inpatients. Executive control impairment appears more prevalent than global cognitive deficits, visuospatial impairment, or depression.

MOSFET sensitivity dependence on integrated dose from high-energy photon beams.

The ability of a commercially available dual bias, dual MOSFET dosimetry system to measure therapeutic doses reproducibly throughout its vendor-defined dose-based lifetime has been evaluated by characterizing its sensitivity variation to integrated/cumulative doses from,high-energy (6 and 15 MV) photon radiotherapy beams. The variation of sensitivity as a function of total integrated dose was studied for three different dose-per-fraction levels; namely, 50, 200, and 1200 cGy/fraction. In standard sensitivity mode (i.e., measurements involving dose-per-fraction levels > or =100 cGy), the response of the MOSFET system to identical irradiations increased with integrated dose for both energies investigated. Dose measurement reproducibility for the low (i.e., 50 cGy) dose fractions was within 2.1% (if the system was calibrated before each in-phantom measurement) and 3.1% [if the system was calibrated prior to first use, with no intermediate calibration(s)]. Similarly, dose measurement reproducibility was between 2.2% and 6.6% for the conventional (i.e., 200 cGy) dose fractions and between 1.8% and 7.9% for escalated (i.e., 1200 cGy) dose fractions. The results of this study suggest that, due to the progressively increasing sensitivity resulting from the dual-MOSFET design, frequent calibrations are required to achieve measurement accuracy of < or =3% (within one standard deviation).

Volumetric image-guidance: does routine usage prompt adaptive re-planning? An institutional review.

PURPOSE: To investigate how the use of volumetric image-guidance using an on-board cone-beam computed tomography (CBCT) system impacts on the frequency of adaptive re-planning. MATERIAL AND METHODS: Treatment courses of 146 patients who have undergone a course of external beam radiation therapy (EBRT) using volumetric CBCT image-guidance were analyzed. Target locations included the brain, head and neck, chest, abdomen, as well as prostate and non-prostate pelvis. The majority of patients (57.5%) were treated with hypo-fractionated treatment regimens (three to 15 fraction courses). The frequency of image-guidance ranged from daily (87.7%) to weekly or twice weekly. The underlying medical necessity for adaptive re-planning as well as frequency and consequences of plan adaptation to dose-volume parameters was assessed. RESULTS: Radiation plans of 34 patients (23.3%) were adapted at least once (up to six time) during their course of EBRT as a result of image-guidance CBCT review. Most common causes for adaptive planning were: tumor change (mostly shrinkage: 10 patients; four patients more than one re-plan), change in abdominal girth (systematic change in hollow organ filling; n=7, two patients more than one re-plan), weight loss (n=5), and systematic target setup deviation from simulation (n=5). Adaptive re-plan was required mostly for conventionally fractionated courses; only 5 patient plans undergoing hypo-fractionated treatment were adjusted. In over 91% of adapted plans, the dose-volume parameters did deviate from the prescribed plan parameters by more than 5% for at least 10% of the target volume, or organs-at-risk in close proximity to the target volume. DISCUSSION: Routine use of volumetric image-guidance has in our practice increased the demand for adaptive re-planning. Volumetric CBCT image-guidance provides sufficient imaging information to reliably predict the need for dose adjustment. In the vast majority of cases evaluated, the initial and adapted dose-volume parameters differed to a degree that was considered clinically significant.

Image-guidance protocol comparison: supine and prone set-up accuracy for pelvic radiation therapy.

PURPOSE: To investigate the impact of prone versus supine patient set-up and use of various image-guidance protocols on residual set-up error for radiation therapy of pelvic malignancies. We aim to identify an optimal frequency and protocol for image-guidance. MATERIALS: Using daily online image-guidance mega-voltage CT data from 30 patients (829 MVCT; 299 prone set-up on belly board, 530 supine set-up), we retrospectively assessed the impact of various image-guidance protocols on residual set-up error. We compared daily image-guidance with three different No Action Level protocols (NAL), alternate day image-guidance with running mean and weekly image-guidance. RESULTS: Of 5 IGRT protocols analyzed, the protocol with the highest imaging frequency, alternate day imaging with a running mean (50% imaging frequency), provided the best set-up error reduction. This protocol would have reduced the average length of 3D corrective vector shifts derived from daily image-guidance from 15.2 and 13.5 mm for prone and supine set-up, to 5 and 5.4 mm, respectively. A NAL protocol, averaging shifts of the first 3 fractions (NAL3), would have reduced the respective set-up variability to 6.3 (prone), and 7.5 mm (supine). An extended NAL (eNAL) protocol, averaging shifts of the first 3 fractions plus weekly imaging, would have reduced the daily positioning variability to 6 mm for both prone and supine set-ups. Daily image-guidance yielded set-up corrections >10 mm in 64.3% for prone and 70.3% for supine position. Use of the NAL3 protocol would have reduced the respective frequency to 14.4%, and 21.2% for prone, and supine positioning. In comparison, the alternate day running mean protocol would have reduced the frequency of shifts >10 mm to 5.5% (prone), and 8.3% (supine), respectively. DISCUSSION: In this comparison, high frequency image-guidance provided the highest benefit with respect to residual set-up errors. However, both NAL and eNAL protocols provided significant set-up error reduction with lowered imaging frequency. While the mean 3D vector of corrective shifts was longer for prone set-up compared to the supine set-up, using any image-guidance protocol would have reduced shifts for prone set-up to a greater extent than for the supine set-up. This indicates a greater risk for systematic set-up errors in prone set-up, and larger random errors using a supine patient set-up.

Evaluation of alignment error due to a speed artifact in stereotactic ultrasound image guidance.

Ultrasound (US) image guidance systems used in radiotherapy are typically calibrated for soft tissue applications, thus introducing errors in depth-from-transducer representation when used in media with a different speed of sound propagation (e.g. fat). This error is commonly referred to as the speed artifact. In this study we utilized a standard US phantom to demonstrate the existence of the speed artifact when using a commercial US image guidance system to image through layers of simulated body fat, and we compared the results with calculated/predicted values. A general purpose US phantom (speed of sound (SOS) = 1540 m s(-1)) was imaged on a multi-slice CT scanner at a 0.625 mm slice thickness and 0.5 mm x 0.5 mm axial pixel size. Target-simulating wires inside the phantom were contoured and later transferred to the US guidance system. Layers of various thickness (1-8 cm) of commercially manufactured fat-simulating material (SOS = 1435 m s(-1)) were placed on top of the phantom to study the depth-related alignment error. In order to demonstrate that the speed artifact is not caused by adding additional layers on top of the phantom, we repeated these measurements in an identical setup using commercially manufactured tissue-simulating material (SOS = 1540 m s(-1)) for the top layers. For the fat-simulating material used in this study, we observed the magnitude of the depth-related alignment errors resulting from the speed artifact to be 0.7 mm cm(-1) of fat imaged through. The measured alignment errors caused by the speed artifact agreed with the calculated values within one standard deviation for all of the different thicknesses of fat-simulating material studied here. We demonstrated the depth-related alignment error due to the speed artifact when using US image guidance for radiation treatment alignment and note that the presence of fat causes the target to be aliased to a depth greater than it actually is. For typical US guidance systems in use today, this will lead to delivery of the high dose region at a position slightly posterior to the intended region for a supine patient. When possible, care should be taken to avoid imaging through a thick layer of fat for larger patients in US alignments or, if unavoidable, the spatial inaccuracies introduced by the artifact should be considered by the physician during the formulation of the treatment plan.

Development of a geometry-based respiratory motion-simulating patient model for radiation treatment dosimetry.

Temporal and spatial anatomical changes caused by respiration during radiation treatment delivery can lead to discrepancies between the prescribed and actually received radiation doses. This paper presents a study to construct a respiratory-motion-simulating, four-dimensional (4D) patient anatomical and dosimetry model for the study of dosimetric effects of organ motion on various radiation treatment plans and delivery strategies. A 3D VIP-Man (VIsible Photographic Man) model has been reconstructed using the Non-Uniform Rational B-Splines (NURBS) method to reflect the deformation of organs during respiration by manipulating surface control points as time-dependent equations. The 4D model is applied to dose simulation using the Monte Carlo code EGS4 (Electron Gamma Shower, version 4). Two delivery scenarios in radiation therapy were simulated: "gating" treatment and 4D "image-guided" treatment. For each delivery scenario, one conformal plan and one Intensity Modulated Radiation Therapy (IMRT) plan were developed. A lesion in the left lung was modeled to investigate the impact of respiratory motion on radiation dose distributions. Based on target dose volume histograms (DVHs), it is demonstrated that it is important to use accurate "gating" to improve the dose distribution. The results also suggest that, during a 4D "image-guided" treatment delivery, monitoring of patient breathing pattern is critical. This study demonstrates the potential of using "standard" motion-simulating patient model for 4D treatment planning and motion management.

Analysis of Magnetic Resonance Image Signal Fluctuations Acquired During MR-Guided Radiotherapy.

Magnetic resonance-guided radiotherapy (MRgRT) is a new and evolving treatment modality that allows unprecedented visualization of the tumor and surrounding anatomy. MRgRT includes daily 3D magnetic resonance imaging (MRI) for setup and rapidly repeated near real-time MRI scans during treatment for target tracking. One of the more exciting potential benefits of MRgRT is the ability to analyze serial MRIs to monitor treatment response or predict outcomes. A typical radiation treatment (RT) over the span of 10-15 minutes on the MRIdian system (ViewRay, Cleveland, OH) yields thousands of "cine" images, each acquired in 250 ms. This unique data allows for a glimpse in image intensity changes during RT delivery. In this report, we analyze cine images from a single fraction RT of a glioblastoma patient on the ViewRay platform in order to characterize the dynamic signal changes occurring during RT therapy. The individual frames in the cines were saved into DICOM format and read into an MIM image analysis platform (MIM Software, Cleveland, OH) as a time series. The three possible states of the three Cobalt-60 radiation sources-OFF, READY, and ON-were also recorded. An in-house Java plugin for MIM was created in order to perform principal component analysis (PCA) on each of the datasets. The analysis resulted in first PC, related to monotonous signal increase over the course of the treatment fraction. We found several distortion patterns in the data that we postulate result from the perturbation of the magnetic field due to the moving metal parts in the platform while treatment was being administered. The largest variations were detected when all Cobalt-60 sources were OFF. During this phase of the treatment, the gantry and multi-leaf collimators (MLCs) are moving. Conversely, when all Cobalt-60 sources were in the ON position, the image signal fluctuations were minimal, relating to very little mechanical motion. At this phase, the gantry, the MLCs, and sources are fixed in their positions. These findings were confirmed in a study with the daily quality assurance (QA) phantom. While the identified variations were not related to physiological processes, our findings confirm the sensitivity of the developed approach to identify very small fluctuations. Relating these variations to the physical changes that occur during treatment shows the methodical ability of the technique to uncover their underlying sources.

Safety and Efficacy of Accelerated Hypofractionation and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma Patients With Varying Degrees of Hepatic Impairment.

PURPOSE: To report the toxicities and outcomes for stereotactic body radiation therapy (SBRT) and accelerated hypofractionated radiation therapy (AHRT) in patients with Child-Pugh (CP) class A, B, or C and albumin-bilirubin (ALBI) score 1, 2, or 3 hepatocellular carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the data from 146 patients with hepatocellular carcinoma who had undergone SBRT (50 Gy in 5 fractions) or AHRT (45 Gy in 18 fractions). The primary endpoint was liver toxicity, defined as an increase in the CP score of ≥2 within 6 months of radiation therapy. The secondary endpoints of ALBI change, overall survival, and local control were also calculated. RESULTS: The median follow-up was 23 months (range 1-59). Most received SBRT (72%), and 28% received AHRT. Of all 146 patients, 45 (31%) had a CP score elevation of ≥2 within 6 months of radiation therapy (RT) (27 patients [28%] with baseline CP-A/B7 and 18 [35%] with baseline CP-B8/B9/C cirrhosis; P = .45). On multivariate analysis, neither baseline CP nor ALBI score was predictive of toxicity. No patient with a decline in liver functionality of CP ≥2 within 6 months of RT returned to baseline at later time points. Eleven grade 4 toxicities were observed. The mean change in the raw ALBI score at ∼6 months was similar for all baseline ALBI groups. Twenty-two patients underwent orthotopic liver transplantation after RT, 13 of whom had baseline CP-B8/B9/C liver functionality. For all patients, the 1- and 2-year treated-lesion local control was greater for SBRT than for AHRT (2-year 94% vs 65%, P < .0001). CONCLUSIONS: The tolerability of SBRT or AHRT as measured by a CP score decline of ≥2 within 6 months of RT was similar across baseline liver functionality groups. Compared with AHRT, SBRT was associated with superior local control. Because the true tolerability of limited-volume RT for patients with CP-B or CP-C cirrhosis is unknown, prospective trials validating its safety and efficacy are warranted.

Gene expression changes in the rodent hippocampus following whole brain irradiation.

Therapeutic cranial irradiation may result in debilitating cognitive impairments. In human patients these deficits are age and radiation dose-dependent and are attributed to a diminished capability to learn and memorize new tasks and information. Because of the known involvement of the hippocampus in memory consolidation, it is important to identify irradiation-induced changes including alterations in gene expression in this structure. Whole brain irradiation doses of 0, 0.3, 3, 10, or 30 Gray (Gy) were administered to 3-month-old rats in a single session. Twenty-four hours following cranial irradiation, hippocampi were processed for oligonucleotide microarrays analysis. Metallothioneins (MT)-I and -II, heat shock protein (Hsp-27), glial fibrillary acidic protein alpha (GFAP), and c-Fos genes were altered significantly across the various doses of irradiation. A pathway analysis shows that these genes were centered around the immediate early gene myc and tumor suppressor gene (TP53). Our results identified important genes and possible pathways that are altered in the hippocampus in the acute phase following cranial irradiation, and implicate gene pathways important for both learning and memory and apoptosis.

Intensity-modulated radiosurgery: improving dose gradients and maximum dose using post inverse-optimization interactive dose shaping.

Intensity-modulated radiosurgery (IMRS) for brain metastases and arterio-venous malformations (AVM) using a serial tomotherapy system (Nomos Corp., Cranberry Township, PA) has been delivered in >150 cases over the last 5 years. A new software tool provided within the Corvus inverse planning software (ActiveRx) allows for post inverse planning re-optimization and individualization of the dose distribution. We analyzed this tool with respect to increasing the steepness of the dose gradient and in-target dose inhomogeneity while maintaining conformity. Fifteen clinically delivered IMRS plans for solitary brain metastases provided the basis for this analysis. The clinical IMRS plans were copied and the ActiveRx module was opened. The toolset in ActiveRx includes a hot spot eraser, a pencil tool to redefine isodose lines and a drag and drop tool, allowing reshaping of existing isodose lines. To assess changes in the steepness of the dose gradient and dose homogeneity, the 100%, 90%, 50% and 25% isodose volume, the volume of the target, maximum dose and mean dose to the target were recorded. We also recorded total monitor units and calculated treatment delivery times. Target volumes ranged from 0.6 to 14.1 cm(3) (mean/median 3.9/1.8 cm(3)). Mean RTOG conformity index (CI) of plans clinically delivered was 1.23+/-0.31; mean homogeneity index (HI) was 115+/-5%. After using the ActiveRx tool-set, the mean CI was slightly improved to 1.14+/-0.1, with an associated increase in HI to 141+/-10%. The average, respective Ian Paddick CI for the 100%, 90% 50% and 25% isodose lines were 0.79 vs. 0.83, 0.44 vs. 0.59, 0.12 vs. 0.19, and 0.04 vs. 0.07, representing significant improvements after using ActiveRx post-optimization. Total MU were reduced by a mean of 12.3% using ActiveRx, shortening estimated treatment delivery times by 3.2 minutes on average. A post inverse planning optimization tool for IMRS plans allowed for statistically significant improvements in the steepness of the dose gradient, and increased maximum and mean target doses compared to clinically delivered plans that were already considered excellent. Gains were especially pronounced in the reduction of normal brain tissue included into the 90%, and 50% isodose lines. We have since made this process part of the clinical routine for all cranial IMRS procedures.

Intensity-modulated Radiosurgery for patients with brain metastases: a mature outcomes analysis.

The purpose of this study was to evaluate the outcomes of patients with brain metastases treated by tomotherapeutic Intensity-modulated Radiosurgery (IMRS). Using retrospective chart review, we analyzed the outcomes of 78 patients (age 33-83 years, median 57 years) who underwent 111 sessions of IMRS (1 to 7 sessions per patient, median 1) for brain metastases (1 to 4 targets per IMRS session, median 1) treated between 2000 and 2005 using a serial tomotherapeutic intensity-modulated radiotherapy treatment (IMRT) planning and delivery system (Peacock, Nomos Corp., Cranberry Township, PA). Treatment planning was performed using an inverse treatment planning optimization algorithm that was optimized for IMRS. A median prescription dose of 15 Gy in combination with WBI, and median 20 Gy for IMRS alone was delivered using 2-4 couch angles over 4-24 rotational arcs. Overall survival was calculated using Kaplan-Meier analysis. To determine the effects of prognostic variables on survival, univariate and multivariate analyses using proportional hazards were performed to assess the effects of age, tumor size, the combination with whole brain irradiation, presence of multiple brain metastases, and presence of extracranial disease. The median overall survival was 6.5 months (95% CI, 5.5-7.9). One- and two-year survival rates were 24% and 10%. In multivariate analyses, age greater than 60 years was the only statistically significant variable that affected survival (hazard rate 1.29, p=0.049). We conclude that tomotherapeutic IMRS is safe and effective to treat patients with brain metastases.

Image-guidance for stereotactic body radiation therapy.

The term stereotactic body radiation therapy (SBRT) describes a recently introduced external beam radiation paradigm by which small lesions outside the brain are treated under stereotactic conditions, in a single or few fractions of high-dose radiation delivery. Similar to the treatment planning and delivery process for cranial radiosurgery, the emphasis is on sparing of adjacent normal tissues through the creation of steep dose gradients. Thus, advanced methods for assuring an accurate relationship between the target volume position and radiation beam geometry, immediately prior to radiation delivery, must be implemented. Such methods can employ imaging techniques such as planar (e.g., x-ray) or volumetric (e.g., computed tomography [CT]) approaches and are commonly summarized under the general term image-guided radiation therapy (IGRT). This review summarizes clinical experience with volumetric and ultrasound based image-guidance for SBRT. Additionally, challenges and potential limitations of pre-treatment image-guidance are presented and discussed.

Image-guided intensity-modulated radiation therapy for gallbladder carcinoma.

PURPOSE: Clinical and technical parameter analysis of patients treated with ultrasound-based image-guided tomotherapeutic IMRT for gallbladder cancer. METHODS AND MATERIALS: Between 8/2001 and 5/2005, 10 patients with primary tumors of the gallbladder were treated by image-guided IMRT to median doses of 59 Gy. To analyze normal tissue radiation exposure reduction using this novel approach, a virtual plan comparison between actually delivered IMRT plans and re-computed plans with identical inverse planning parameters but more conventional PTV safety margins was conducted. RESULTS: Average CTV was 379 cm(3), with a mean initial PTV of 834 cm(3). In 9/10 patients, a boost was delivered to a mean CTV(boost) of 171 cm(3) and average PTV(boost) of 241 cm(3). One patient reported RTOG grade 3 acute toxicity. All other patients exhibited Grade 2 or lower acute toxicity. Preliminary median overall survival was 16.7 months (range 3.2-34.9 months), with 5/10 patients alive at analysis. Virtual plan comparison revealed significant organ-at-risk sparing by the enabled PTV margin reduction. CONCLUSION: Ultrasound-based image-guided IMRT is a feasible mechanism of delivering conformal radiation doses to tumors of the gallbladder with acceptable toxicity. Early outcome data with this novel radiation planning and delivery technique are encouraging and comparable to previously reported literature.