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.

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.

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.

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.

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.

The impact of anatomic tumor location on inter-fraction tumor motion during lung stereotactic body radiation therapy (SBRT).

PURPOSE: Narrow PTV margins and steep dose gradients underscore the importance of evaluating breathing-associated tumor motion for lung SBRT. The specific aim of this study was to determine the impact of anatomic tumor location on inter-fraction tumor motion. METHODS AND MATERIALS: Forty-one patients underwent standard free-breathing 4DCT simulation and daily image-guidance 4DCTs during lung SBRT. Absolute tumor motion amplitude in the mediolateral (ML), anterior-posterior (AP), and superior-inferior (SI) directions was analyzed from 159 total 4DCT scans (simulation and daily pre-treatment). RESULTS: Overall, the inter-fraction tumor motion amplitude in the ML, AP, and SI directions was small (mean ≤2.5 mm). Similarly, while both upper lobe (UL) and lower lobe (LL) tumors exhibited limited inter-fraction motion in both the ML and AP directions (mean ≤2.2 mm), tumors in the LL had increased inter-fraction motion in the SI direction compared to UL tumors (mean 4.3±4.0 mm vs. 1.7±1.7 mm, p=0.008). Moreover, 28.6% (n=4) of LL tumors exhibited mean inter-fraction motion along the SI direction >5 mm (all of which resided in the supra-diaphragmatic basal segments of the LL). CONCLUSIONS: Mean inter-fraction tumor motion amplitude along the SI direction exceeded our PTV margins (an isotropic 5 mm expansion of the ITV) in 28.6% of LL tumors (all of which resided in the basal segments). These results suggest that typical ITV-to-PTV margins may be insufficient for a subset of LL lesions and that increased PTV margins, daily breathing motion re-assessment and/or adaptive re-planning may benefit patients with supra-diaphragmatic tumors in the LL.

Volumetric-modulated arc radiotherapy for pancreatic malignancies: dosimetric comparison with sliding-window intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy.

Volumetric-modulated arc radiotherapy (VMAT) is an iteration of intensity-modulated radiotherapy (IMRT), both of which deliver highly conformal dose distributions. Studies have shown the superiority of VMAT and IMRT in comparison with 3-dimensional conformal radiotherapy (3D-CRT) in planning target volume (PTV) coverage and organs-at-risk (OARs) sparing. This is the first study examining the benefits of VMAT in pancreatic cancer for doses more than 55.8 Gy. A planning study comparing 3D-CRT, IMRT, and VMAT was performed in 20 patients with pancreatic cancer. Treatments were planned for a 25-fraction delivery of 45 Gy to a large field followed by a reduced-volume 8-fraction external beam boost to 59.4 Gy in total. OARs and PTV doses, conformality index (CI) deviations from 1.0, monitor units (MUs) delivered, and isodose volumes were compared. IMRT and VMAT CI deviations from 1.0 for the large-field and the boost plans were equivalent (large field: 0.032 and 0.046, respectively; boost: 0.042 and 0.037, respectively; p > 0.05 for all comparisons). Both IMRT and VMAT CI deviations from 1.0 were statistically superior to 3D-CRT (large field: 0.217, boost: 0.177; p < 0.05 for all comparisons). VMAT showed reduction of the mean dose to the boost PTV (VMAT: 61.4 Gy, IMRT: 62.4 Gy, and 3D-CRT: 62.3 Gy; p < 0.05). The mean number of MUs per fraction was significantly lower for VMAT for both the large-field and the boost plans. VMAT delivery time was less than 3 minutes compared with 8 minutes for IMRT. Although no statistically significant dose reduction to the OARs was identified when comparing VMAT with IMRT, VMAT showed a reduction in the volumes of the 100% isodose line for the large-field plans. Dose escalation to 59.4 Gy in pancreatic cancer is dosimetrically feasible with shorter treatment times, fewer MUs delivered, and comparable CIs for VMAT when compared with IMRT.

Electromagnetic navigational bronchoscopy-guided fiducial markers for lung stereotactic body radiation therapy: analysis of safety, feasibility, and interfraction stability.

BACKGROUND: Embolization coils as fiducial markers for pulmonary stereotactic body radiation therapy (SBRT) are perceived to be the optimal marker type, given their ability to conform and anchor within the small airways. The aim of our study was to assess retention, placement, migration, feasibility, and safety of electromagnetic navigational bronchoscopy (ENB)-guided embolization coil markers throughout courses of SBRT. METHODS: Thirty-one patients with 34 nodules underwent ENB-guided fiducial placement of several 4 mm fibered platinum embolization coils before SBRT. Patient and nodule positioning was confirmed with daily pretreatment cone-beam computed tomography (CBCT). Fiducial positional characteristics were analyzed utilizing radiation treatment-planning software comparing the simulation CT with daily CBCTs. RESULTS: Of 105 fiducials placed, 103 were identifiable on simulation CT (retention rate: 98.1%). Incidence of asymptomatic pneumothoraces was 6%. One patient experienced hemoptysis requiring hospitalization. Eighty-six percent of fiducials were placed within 1 cm of the nodule, with 52% of fiducials placed directly on the nodule surface. Throughout a 5-fraction SBRT course, fiducial displacement was <7, 5, and 2 mm in 98%, 96%, and 67% of pretreatment CBCTs. CONCLUSIONS: ENB placement of embolization coils as fiducials for lung SBRT image guidance is associated with a low rate of iatrogenic pneumothoraces, and resulted in reliable placement of the fiducials in close proximity to the lung nodule. Embolization coils retained their relative position to the nodule throughout the course of SBRT, and provide an excellent alternative to linear gold seeds.

Real-time prostate motion assessment: image-guidance and the temporal dependence of intra-fraction motion.

BACKGROUND: The rapid adoption of image-guidance in prostate intensity-modulated radiotherapy (IMRT) results in longer treatment times, which may result in larger intrafraction motion, thereby negating the advantage of image-guidance. This study aims to qualify and quantify the contribution of image-guidance to the temporal dependence of intrafraction motion during prostate IMRT. METHODS: One-hundred and forty-three patients who underwent conventional IMRT (n=67) or intensity-modulated arc therapy (IMAT/RapidArc, n=76) for localized prostate cancer were evaluated. Intrafraction motion assessment was based on continuous RL (lateral), SI (longitudinal), and AP (vertical) positional detection of electromagnetic transponders at 10 Hz. Daily motion amplitudes were reported as session mean, median, and root-mean-square (RMS) displacements. Temporal effect was evaluated by categorizing treatment sessions into 4 different classes: IMRTc (transponder only localization), IMRTcc (transponder + CBCT localization), IMATc (transponder only localization), or IMATcc (transponder + CBCT localization). RESULTS: Mean/median session times were 4.15/3.99 min (IMATc), 12.74/12.19 min (IMATcc), 5.99/5.77 min (IMRTc), and 12.98/12.39 min (IMRTcc), with significant pair-wise difference (p<0.0001) between all category combinations except for IMRTcc vs. IMATcc (p>0.05). Median intrafraction motion difference between CBCT and non-CBCT categories strongly correlated with time for RMS (t-value=17.29; p<0.0001), SI (t-value=-4.25; p<0.0001), and AP (t-value=2.76; p<0.0066), with a weak correlation for RL (t-value=1.67; p=0.0971). Treatment time reduction with non-CBCT treatment categories showed reductions in the observed intrafraction motion: systematic error (Σ)<0.6 mm and random error (σ)<1.2 mm compared with ≤0.8 mm and <1.6 mm, respectively, for CBCT-involved treatment categories. CONCLUSIONS: For treatment durations >4-6 minutes, and without any intrafraction motion mitigation protocol in place, patient repositioning is recommended, with at least the acquisition of the lateral component of an orthogonal image pair in the absence of volumetric imaging.

Circumferential or sectored beam arrangements for stereotactic body radiation therapy (SBRT) of primary lung tumors: effect on target and normal-structure dose-volume metrics.

To compare 2 beam arrangements, sectored (beam entry over ipsilateral hemithorax) vs circumferential (beam entry over both ipsilateral and contralateral lungs), for static-gantry intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) delivery techniques with respect to target and organs-at-risk (OAR) dose-volume metrics, as well as treatment delivery efficiency. Data from 60 consecutive patients treated using stereotactic body radiation therapy (SBRT) for primary non-small-cell lung cancer (NSCLC) formed the basis of this study. Four treatment plans were generated per data set: IMRT/VMAT plans using sectored (-s) and circumferential (-c) configurations. The prescribed dose (PD) was 60Gy in 5 fractions to 95% of the planning target volume (PTV) (maximum PTV dose ~ 150% PD) for a 6-MV photon beam. Plan conformality, R50 (ratio of volume circumscribed by the 50% isodose line and the PTV), and D2cm (Dmax at a distance ≥2cm beyond the PTV) were evaluated. For lungs, mean doses (mean lung dose [MLD]) and percent V30/V20/V10/V5Gy were assessed. Spinal cord and esophagus Dmax and D5/D50 were computed. Chest wall (CW) Dmax and absolute V30/V20/V10/V5Gy were reported. Sectored SBRT planning resulted in significant decrease in contralateral MLD and V10/V5Gy, as well as contralateral CW Dmax and V10/V5Gy (all p < 0.001). Nominal reductions of Dmax and D5/D50 for the spinal cord with sectored planning did not reach statistical significance for static-gantry IMRT, although VMAT metrics did show a statistically significant decrease (all p < 0.001). The respective measures for esophageal doses were significantly lower with sectored planning (p < 0.001). Despite comparable dose conformality, irrespective of planning configuration, R50 significantly improved with IMRT-s/VMAT-c (p < 0.001/p = 0.008), whereas D2cm significantly improved with VMAT-c (p < 0.001). Plan delivery efficiency improved with sectored technique (p < 0.001); mean monitor unit (MU)/cGy of PD decreased from 5.8 ± 1.9 vs 5.3 ± 1.7 (IMRT) and 2.7 ± 0.4 vs 2.4 ± 0.3 (VMAT). The sectored configuration achieves unambiguous dosimetric advantages over circumferential arrangement in terms of esophageal, contralateral CW, and contralateral lung sparing, in addition to being more efficient at delivery.

Dosimetric comparison of patient setup strategies in stereotactic body radiation therapy for lung cancer.

PURPOSE: In this work, the authors retrospectively compared the accumulated dose over the treatment course for stereotactic body radiation therapy (SBRT) of lung cancer for three patient setup strategies. METHODS: Ten patients who underwent lung SBRT were selected for this study. At each fraction, patients were immobilized using a vacuum cushion and were CT scanned. Treatment plans were performed on the simulation CT. The planning target volume (PTV) was created by adding a 5-mm uniform margin to the internal target volume derived from the 4DCT. All plans were normalized such that 99% of the PTV received 60 Gy. The plan parameters were copied onto the daily CT images for dose recalculation under three setup scenarios: skin marker, bony structure, and soft tissue based alignments. The accumulated dose was calculated by summing the dose at each fraction along the trajectory of a voxel over the treatment course through deformable image registration of each CT with the planning CT. The accumulated doses were analyzed for the comparison of setup accuracy. RESULTS: The tumor volume receiving 60 Gy was 91.7 ± 17.9%, 74.1 ± 39.1%, and 99.6 ± 1.3% for setup using skin marks, bony structures, and soft tissue, respectively. The isodose line covering 100% of the GTV was 55.5 ± 7.1, 42.1 ± 16.0, and 64.3 ± 7.1 Gy, respectively. The corresponding average biologically effective dose of the tumor was 237.3 ± 29.4, 207.4 ± 61.2, and 258.3 ± 17.7 Gy, respectively. The differences in lung biologically effective dose, mean dose, and V20 between the setup scenarios were insignificant. CONCLUSIONS: The authors' results suggest that skin marks and bony structure are insufficient for aligning patients in lung SBRT. Soft tissue based alignment is needed to match the prescribed dose delivered to the tumors.

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.

Assessment of planning target volume margins for intensity-modulated radiotherapy of the prostate gland: role of daily inter- and intrafraction motion.

PURPOSE: To determine planning target volume margins for prostate intensity-modulated radiotherapy based on inter- and intrafraction motion using four daily localization techniques: three-point skin mark alignment, volumetric imaging with bony landmark registration, volumetric imaging with implanted fiducial marker registration, and implanted electromagnetic transponders (beacons) detection. METHODS AND MATERIALS: Fourteen patients who underwent definitive intensity-modulated radiotherapy for prostate cancer formed the basis of this study. Each patient was implanted with three electromagnetic transponders and underwent a course of 39 treatment fractions. Daily localization was based on three-point skin mark alignment followed by transponder detection and patient repositioning. Transponder positioning was verified by volumetric imaging with cone-beam computed tomography of the pelvis. Relative motion between the prostate gland and bony anatomy was quantified by offline analyses of daily cone-beam computed tomography. Intratreatment organ motion was monitored continuously by the Calypso® System for quantification of intrafraction setup error. RESULTS: As expected, setup error (that is, inter- plus intrafraction motion, unless otherwise stated) was largest with skin mark alignment, requiring margins of 7.5 mm, 11.4 mm, and 16.3 mm, in the lateral (LR), longitudinal (SI), and vertical (AP) directions, respectively. Margin requirements accounting for intrafraction motion were smallest for transponder detection localization techniques, requiring margins of 1.4 mm (LR), 2.6 mm (SI), and 2.3 mm (AP). Bony anatomy alignment required 2.1 mm (LR), 9.4 mm (SI), and 10.5 mm (AP), whereas image-guided marker alignment required 2.8 mm (LR), 3.7 mm (SI), and 3.2 mm (AP). No marker migration was observed in the cohort. CONCLUSION: Clinically feasible, rapid, and reliable tools such as the electromagnetic transponder detection system for pretreatment target localization and, subsequently, intratreatment target location monitoring allow clinicians to reduce irradiated volumes and facilitate safe dose escalation, where appropriate.

Ionizing radiation impairs the formation of trace fear memories and reduces hippocampal neurogenesis.

Long-term cognitive impairments are a feared consequence of therapeutic cranial irradiation in children as well as adults. Studies in animal models suggest that these deficits may be associated with a decrease in hippocampal granule cell proliferation and survival. In the present study the authors examined whether whole brain irradiation would affect trace fear conditioning, a hippocampal-dependent task. Preadolescent (postnatal Day 21, PD 21), adolescent (PD 50), and postadolescent (PD 70) rats received single doses of 0 Gray (Gy), 0.3 Gy, 3 Gy, or 10 Gy whole brain irradiation. Three months after radiation treatment, a significant dose-dependent decrease in bromo-deoxyuridine positive cells was observed. Irradiation produced a dose-dependent decrease in freezing in response to the conditioned stimulus in all age groups. Interestingly, the authors found no differences in context freezing between irradiated and control groups. Further, there were no differences in delay fear memories, which are independent of hippocampus function. Our results strongly indicate that irradiation impairs associative memories dependent on hippocampus and this deficit is accompanied by a decrease in granule cell neurogenesis indicating that these cells may be involved in normal hippocampal memory function.

Implications of a high-definition multileaf collimator (HD-MLC) on treatment planning techniques for stereotactic body radiation therapy (SBRT): a planning study.

PURPOSE: To assess the impact of two multileaf collimator (MLC) systems (2.5 and 5 mm leaf widths) on three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and dynamic conformal arc techniques for stereotactic body radiation therapy (SBRT) of liver and lung lesions. METHODS: Twenty-nine SBRT plans of primary liver (n=11) and lung (n=18) tumors were the basis of this study. Five-millimeter leaf width 120-leaf Varian Millennium (M120) MLC-based plans served as reference, and were designed using static conformal beams (3DCRT), sliding-window intensity-modulated beams (IMRT), or dynamic conformal arcs (DCA). Reference plans were either re-optimized or recomputed, with identical planning parameters, for a 2.5-mm width 120-leaf BrainLAB/Varian high-definition (HD120) MLC system. Dose computation was based on the anisotropic analytical algorithm (AAA, Varian Medical Systems) with tissue heterogeneity taken into account. Each plan was normalized such that 100% of the prescription dose covered 95% of the planning target volume (PTV). Isodose distributions and dose-volume histograms (DVHs) were computed and plans were evaluated with respect to target coverage criteria, normal tissue sparing criteria, as well as treatment efficiency. RESULTS: Dosimetric differences achieved using M120 and the HD120 MLC planning were generally small. Dose conformality improved in 51.7%, 62.1% and 55.2% of the IMRT, 3DCRT and DCA cases, respectively, with use of the HD120 MLC system. Dose heterogeneity increased in 75.9%, 51.7%, and 55.2% of the IMRT, 3DCRT and DCA cases, respectively, with use of the HD120 MLC system. DVH curves demonstrated a decreased volume of normal tissue irradiated to the lower (90%, 50% and 25%) isodose levels with the HD120 MLC. CONCLUSION: Data derived from the present comparative assessment suggest dosimetric merit of the high definition MLC system over the millennium MLC system. However, the clinical significance of these results warrants further investigation in order to determine whether the observed dosimetric advantages translate into outcome improvements.

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.

Image-guided intensity-modulated radiotherapy (IG-IMRT) for biliary adenocarcinomas: Initial clinical results.

PURPOSE: Biliary tract lesions are comparatively rare neoplasms, with ambiguous indications for radiotherapy. The specific aim of this study was to report the clinical results of a single-institution biliary tract series treated with modern radiotherapeutic techniques, and detail results using both conventional and image-guided intensity-modulated radiation therapy (IG-IMRT). METHODS AND MATERIALS: From 2001 to 2005, 24 patients with primary adenocarcinoma of the biliary tract (gallbladder and extrahepatic bile ducts) were treated by IG-IMRT. To compare outcomes, data from a sequential series of 24 patients treated between 1995 and 2005 with conventional radiotherapy (CRT) techniques were collected as a comparator set. Demographic and treatment parameters were collected. Endpoints analyzed included treatment-related acute toxicity and survival. RESULTS: Median estimated survival for all patients completing treatment was 13.9 months. A statistically significant higher mean dose was given to patients receiving IG-IMRT compared to CRT, 59 vs. 48Gy. IG-IMRT and CRT cohorts had a median survival of 17.6 and 9.0 months, respectively. Surgical resection was associated with improved survival. Two patients (4%) experienced an RTOG acute toxicity score>2. The most commonly reported GI toxicities (RTOG Grade 2) were nausea or diarrhea requiring oral medication, experienced by 46% of patients. CONCLUSION: This series presents the first clinical outcomes of biliary tract cancers treated with IG-IMRT. In comparison to a cohort of patients treated by conventional radiation techniques, IG-IMRT was feasible for biliary tract tumors, warranting further investigation in prospective clinical trials.

Optimization of isocenter location for intensity modulated stereotactic treatment of small intracranial targets.

PURPOSE: To quantify the impact of isocenter location on treatment plan quality for intensity-modulated stereotactic treatment of small intracranial lesions. METHODS AND MATERIALS: For 18 patients previously treated by stereotactic-intensity modulated radiosurgery (IMRS) or intensity-modulated radiation therapy (IMRT), a retrospective virtual planning study was conducted wherein the impact of isocenter location on plan quality was measured. Treatment indications studied included six arteriovenous malformations, six acoustic neuromas, and six intracranial metastases, ranging in volume from 0.71 to 3.21 cm(3) (mean = 2.26 cm(3)), 1.08 to 2.84 cm(3) (mean = 1.73 cm(3)), and 0.19 to 2.30 cm(3) (mean = 0.79 cm(3)), respectively. Variation of isocenter location causes the geometric grid of pencil beams into which the target is segmented for intensity-modulated treatment to be altered. The impact of this pencil-beam-grid redefinition on achievable conformity index was quantified for three collimators (Varian Millennium 120; BrainLab MM3; Nomos binary Mimic) and three treatment planning systems (TPS; Varian Eclipse v6.5; BrainLab BrainScan v5.31; Best-Nomos Corvus v6.2), resulting in the evaluation of 3,446 treatment plans. RESULTS: For all patients, collimator, and TPS combinations studied, a significant variation in plan quality was observed as a function of isocenter and pencil-beam-grid relocation. Optimization of isocenter location resulted in treatment plan conformity variations as large as 109% (min = 15%, mean = 51%, max = 109%). CONCLUSION: Optimization of isocenter location for IMRT/IMRS treatment of small intracranial lesions in which pencil-beam dimensions are comparable to target dimensions, can result in significant improvements in treatment plan quality.

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.