2D antiscatter grid and scatter sampling based CBCT method for online dose calculations during CBCT guided radiation therapy of pelvis.

BACKGROUND: Online dose calculations before the delivery of radiation treatments have applications in dose delivery verification, online adaptation of treatment plans, and simulation-free treatment planning. While dose calculations by directly utilizing CBCT images are desired, dosimetric accuracy can be compromised due to relatively lower HU accuracy in CBCT images. PURPOSE: In this work, we propose a novel CBCT imaging pipeline to enhance the accuracy of CBCT-based dose calculations in the pelvis region. Our approach aims to improve the HU accuracy in CBCT images, thereby improving the overall accuracy of CBCT-based dose calculations prior to radiation treatment delivery. METHODS: An in-house developed quantitative CBCT pipeline was implemented to address the CBCT raw data contamination problem. The pipeline combines algorithmic data correction strategies and 2D antiscatter grid-based scatter rejection to achieve high CT number accuracy. To evaluate the effect of the quantitative CBCT pipeline on CBCT-based dose calculations, phantoms mimicking pelvis anatomy were scanned using a linac-mounted CBCT system, and a gold standard multidetector CT used for treatment planning (pCT). A total of 20 intensity-modulated treatment plans were generated for five targets, using 6 and 10 MV flattening filter-free beams, and utilizing small and large pelvis phantom images. For each treatment plan, four different dose calculations were performed using pCT images and three CBCT imaging configurations: quantitative CBCT, clinical CBCT protocol, and a high-performance 1D antiscatter grid (1D ASG). Subsequently, dosimetric accuracy was evaluated for both targets and organs at risk as a function of patient size, target location, beam energy, and CBCT imaging configuration. RESULTS: When compared to the gold-standard pCT, dosimetric errors in quantitative CBCT-based dose calculations were not significant across all phantom sizes, beam energies, and treatment sites. The largest error observed was 0.6% among all dose volume histogram metrics and evaluated dose calculations. In contrast, dosimetric errors reached up to 7% and 97% in clinical CBCT and high-performance ASG CBCT-based treatment plans, respectively. The largest dosimetric errors were observed in bony targets in the large phantom treated with 6 MV beams. The trends of dosimetric errors in organs at risk were similar to those observed in the targets. CONCLUSIONS: The proposed quantitative CBCT pipeline has the potential to provide comparable dose calculation accuracy to the gold-standard planning CT in photon radiation therapy for the abdomen and pelvis. These robust dose calculations could eliminate the need for density overrides in CBCT images and enable direct utilization of CBCT images for dose delivery monitoring or online treatment plan adaptations before the delivery of radiation treatments.

A 2D antiscatter grid and scatter sampling based CBCT method for online dose calculations during CBCT guided radiation therapy of pelvis.

Online dose calculations before radiation treatment have applications in dose delivery verification, plan adaptation, and treatment planning. We propose a novel CBCT imaging pipeline to enhance accuracy. Our approach aims to improve HU accuracy in CBCT images for more precise dose calculations. A quantitative CBCT pipeline was implemented, combining data correction strategies and scatter rejection, achieving high CT number accuracy. We evaluated the pipeline's effect using pelvis anatomy phantoms and found that dosimetric errors in quantitative CBCT-based dose calculations were minimal. In contrast, clinical CBCT and high-performance ASG CBCT-based plans showed significant errors. The proposed quantitative CBCT pipeline offers comparable dose calculation accuracy to the gold-standard planning CT, eliminating the need for density overrides and enabling precise dose delivery monitoring or online plan adaptations in radiation therapy.

The Kelowna template for combined intracavitary and interstitial brachytherapy for gynecologic malignancies: Design, application, treatment planning, dosimetric and treatment outcomes.

PURPOSE: We report the feasibility, experience, and early outcomes of the combined intracavitary and interstitial dedicated applicator using the Kelowna GYN template (Varian, Palo Alto, CA). METHODS AND MATERIALS: The Kelowna GYN template is CT compatible and used for the treatment of gynecologic cancers. In cases with patients that have an intact uterus, a modified applicator system using the Kelowna GYN template and a 3D printed adapter piece allows for compatibility with an intrautaerine tandem. RESULTS: We reviewed the treatment course of 23 patients comprising of 86 fractions of HDR treatment. Median D90 for cervical tumors (n = 7) was 82.4 Gy (range 77.7-92.6); for postoperative cervical tumors (n = 2) was 73.9 Gy (range 72.0-5.8); for vaginal tumors (n = 4) was 85.8 Gy (range 79.8-88.1); for recurrent endometrial (n = 10) was 86.9 Gy (range 74.8-103.2). Median EQD2 D2cc for bladder was 72.4 Gy (range 47.7-99.4), for rectum was 61.2 Gy (range 52.4-80.6), and for sigmoid colon of 50.5 Gy (44.3-66.9). At a median follow-up of 12 months, 2 patients had a local recurrence. Two patients had distant recurrence: one with carcinomatosis at 6 months, and one with pulmonary metastases at 3 months. No patients had late grade three toxicities. CONCLUSIONS: Our single institutional experience supports the use of the Kelowna template as a robust system as a combined IC-IS applicator resulting in versatile and reproducible implants for a variety of gynecologic malignancies.

Gynecologic interstitial brachytherapy curriculum using a low-cost phantom with ultrasound workshop and a treatment planning workshop is effective.

PURPOSE/OBJECTIVE(S): Standardized simulation training geared towards interstitial brachytherapy (IS BT) for gynecologic malignancies is lacking in radiation oncology resident education. We developed and implemented a curriculum for IS BT training with (1) lecture on equipment, workflow, and guidelines, (2) hands-on ultrasound-guided IS BT workshop, and (3) treatment planning workshop. METHODS AND MATERIAL: The cost in materials of each phantom was approximately $66. After a lecture, two alternating workshops were performed. The first session consisted of a hands-on ultrasound-guided IS BT workshop with one resident imaging the phantom with a transabdominal ultrasound probe and the other resident implanting the phantom with needles. A second session consisted of a hands-on treatment planning workshop using BrachyVision and an l-Q spreadsheet with the following objectives: coverage goal, meeting D2cc constraints, and minimizing V200. The primary outcome was improvement in knowledge assessed with Likert-style questions and objective knowledge-based questions (KBQs). RESULTS: Four of the seven medical residents that participated in this curriculum had prior IS BT experience. Residents reported significantly improved knowledge regarding gynecologic IS BT equipment and procedure, evaluating gynecologic anatomy using ultrasound, CT simulation, contouring, and plan review (overall median pre-session subjective score 2 (1) -(3) versus post-session score 4 (3) -(4, p < 0.01). Residents demonstrated improvement in answering KBQs correctly from 44% correct at baseline to 88% after completion of the curriculum (p < 0.01). All residents "Agree" and "Strongly Agree" the session was an effective learning experience. CONCLUSIONS: Residents participating in phantom training with an ultrasound curriculum and a treatment planning session is effective for improving knowledge and skills in IS BT for radiation oncology residents.

Practical Implementation of Emergent After-Hours Radiation Treatment Process Using Remote Treatment Planning on Optimized Diagnostic CT Scans.

The purpose of this report is to present the implementation of a process for after-hours radiation treatment (RT) utilizing remote treatment planning based on optimized diagnostic computed tomography (CT) scans for the urgent palliative treatment of inpatients. A standardized operating procedure was developed by an interprofessional panel to improve the quality of after-hours RT and minimize the risk of treatment errors. A new diagnostic CT protocol was created that could be performed after-hours on hospital scanners and would ensure a reproducible patient position and adequate field of view. An on-call structure for dosimetry staff was created utilizing remote treatment planning. The optimized CT protocol was developed in collaboration with the radiology department, and a novel order set was created in the electronic health system. The clinical workflow begins with the radiation oncologist notifying the on-call team (therapist, dosimetrist, and physicist) and obtaining an optimized diagnostic CT scan on a hospital-based scanner. The dosimetrist remotely creates a plan; the physicist checks the plan; and the patient is treated. Plans are intentionally simple (parallel opposed fields, symmetric jaws) to expedite care and reduce the risk of error. Education on the new process was provided for all relevant staff. Our process was successfully implemented with the use of an optimized CT protocol and remote treatment planning. This approach has the potential to improve the quality and safety of emergent after-hours RT by better approximating the normal process of care.

The Current State of Physics Plan Review Training in Medical Physics Residency Programs in North America.

PURPOSE: This study aimed to identify the current state of residency training in physics plan reviews. METHODS AND MATERIALS: A voluntary, anonymous survey was sent to all program directors of accredited therapeutic medical physics residency programs in North America. Survey questions were developed to determine whether and how residents are trained in physics plan reviews. Survey questions were developed using expert validation and cognitive pretesting. RESULTS: Using a prospectively approved study (COMIRB 18-1073), responses were collected from 70 program directors, representing a 70% response rate. All respondents (100%) designated patient safety to be the purpose of physics plan reviews. Of the respondents, 94% indicated that physicists should first receive training in physics plan reviews while in a residency program. The vast majority of respondents (99%) provide training to residents in physics plan reviews. Although 57 programs (81% of respondents) have residents perform physics plan reviews as part of clinical practice (with varying levels of independence), 13 programs (19% of respondents) do not. The majority of respondents use the following training methods: observe staff physicists (96%), perform supervised reviews on actual patients for training or clinical practice (93%), use a checklist (80%), and read reference materials (62%). Although simulation plans with embedded errors would be implemented by 71% of respondents, they are currently used in only 19% of programs. CONCLUSIONS: The present study is the first to characterize chart-check teaching practices in medical physics residency programs. The vast majority of programs currently train residents in physics plan reviews. The most common teaching methods are observing and performing physics plan reviews, but there is variability in the level of resident involvement in clinical practice for physics plan reviews. There is room for the field to consider advancing current training methods, which is especially important given the critical roles that physics plan reviews have with regard to patient safety.

Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4.

PURPOSE: Patients with human EGFR2-positive (HER2+) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity. EXPERIMENTAL DESIGN: Patients with breast cancer who were ≤45 years regardless of HER2 status or had HER2+ disease regardless of age and underwent SRS for brain metastases were included. Rates of CSRN, SRS data, and details of T-DM1 administration were recorded. Proliferation and astrocytic swelling studies were performed to elucidate mechanisms of toxicity. RESULTS: A total of 45 patients were identified; 66.7% were HER2+, and 60.0% were ≤ 45 years old. Of the entire cohort, 10 patients (22.2%) developed CSRN, 9 of whom received T-DM1. CSRN was observed in 39.1% of patients who received T-DM1 versus 4.5% of patients who did not. Receipt of T-DM1 was associated with a 13.5-fold (P = 0.02) increase in CSRN. Mechanistically, T-DM1 targeted reactive astrocytes and increased radiation-induced cytotoxicity and astrocytic swelling via upregulation of Aquaporin-4 (Aqp4). CONCLUSIONS: The strong correlation between development of CSRN after SRS and T-DM1 warrants prospective studies controlling for variations in timing of T-DM1 and radiation dosing to further stratify risk of CSRN and mitigate toxicity. Until such studies are completed, we advise caution in the combination of SRS and T-DM1.

Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases.

INTRODUCTION: Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. METHODS: We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery. RESULTS: Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0). CONCLUSIONS: Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.

Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non-Small Cell Lung Cancer.

INTRODUCTION: Patients with brain metastases (BMs) arising from EGFR-mutated and anaplastic lymphoma kinase gene (ALK)-rearranged NSCLC have a favorable prognosis compared with patients with non-oncogene-addicted NSCLC, emphasizing the importance of minimizing toxicities such as the cognitive sequelae of whole brain radiation therapy (WBRT). Although radiosurgery without WBRT is the preferred strategy for one to three BMs, this paradigm remains controversial for patients with multiple BMs. METHODS: We reviewed the cases of patients with EGFR-mutated and ALK-rearranged NSCLC presenting to our cancer center between 2008 and 2017 and included only patients receiving treatment to four or more BMs in a single radiosurgery session. RESULTS: We identified 35 patients with a median follow-up of 4.1 years. The maximum number of BMs treated in a single radiosurgery session ranged from four to 26 (median number of BM treated per radiosurgery course: 6), and in total over all courses the number ranged from four to 47 (median: 10). The median survival was 3.0 years (4.2 for ALK-rearranged NSCLC; 2.4 for EGFR-mutated NSCLC) from the diagnosis of BM, and survival was comparable regardless of number of radiosurgery courses, number of BMs treated in total, or number of BMs treated in a single radiosurgery session. The mean hippocampal and whole-brain doses were exceedingly low even for patients receiving treatment to more than 10 BMs (1.2 and 0.8 Gy, respectively). Radiosurgery was well tolerated overall and the 5-year rate of freedom from neurologic death was 84%. The 5-year rate of freedom from WBRT was 97%. CONCLUSIONS: Radiosurgery for multiple BMs is controversial, yet patients with EGFR-mutated and ALK-rearranged NSCLC may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for patients with oncogene-addicted NSCLC with four or more BMs.

A Multi-institution, Retrospective Analysis of Cervix Intracavitary Brachytherapy Treatments. Part 1: Is EQD2 Good Enough for Reporting Radiobiological Effects?

PURPOSE: When brachytherapy doses are reported or added, biologically effective dose (BED) minimum dose covering 90% of the volume (D90) is used as if dose is delivered uniformly to the target. Unlike BED(D90), equivalent uniform BED (EUBED) and generalized biologically equivalent uniform dose (gBEUD) are quantities that integrate dose inhomogeneity. Here we compared BED(D90) and equivalent uniform BED (EUBED)/gBEUD in 3 settings: (1) 2 sites using tandem and ovoid (T&O) but different styles of implants; (2) 2 sites using different devices-T&O and tandem and ring (T&R)-and different styles; and (3) the same site using T&O and T&R with the same style. METHODS AND MATERIALS: EUBED and gBEUD were calculated for 260 fractions from 3 institutions using BED(α/ß = 10 Gy). EUBED uses an extra parameter α with smaller values associated with radioresistant tumors. Similarly, gBEUD uses a, which places variable emphasis on hot/cold spots. Distributions were compared using the Kolmogorov-Smirnoff test at 5% significance. RESULTS: For the 2 sites using T&O, the distribution of EUBED-BED(D90) was not different for values of α = 0.5 to 0.3 Gy-1 but was statistically different for values of α = 0.15 to 0.05 Gy-1 (P=.01, .002). The mean percentage differences between EUBED and BED(D90) ranged from 20% to 100% for α = 0.5 Gy-1 to 0.05 Gy-1. Using gBEUD-BED(D90), the P values indicate the distributions to be similar for a = -10 but to be significantly different for other values of a (-5, -1, 1). Between sites and at the same site using T&O versus T&R, the distributions were statistically different with EUBED/gBEUD irrespective of parameter values at which these quantities were computed. These differences indicate that EUBED/gBEUD capture differences between the techniques and applicators that are not detected by the BED(D90). CONCLUSIONS: BED(D90) is unable to distinguish between plans created by different devices or optimized differently. EUBED/gBEUD distinguish between dose distributions created by different devices and styles of implant and planning. This discrepancy is particularly important with the increased use of magnetic resonance imaging and hybrid devices, whereby one has the ability to create dose distributions that are significant departures from the classic pear.

A complete 4DCT-ventilation functional avoidance virtual trial: Developing strategies for prospective clinical trials.

INTRODUCTION: 4DCT-ventilation is an exciting new imaging modality that uses 4DCT data to calculate lung-function maps. Because 4DCTs are acquired as standard of care for lung cancer patients undergoing radiotherapy, 4DCT-ventiltation provides functional information at no extra dosimetric or monetary cost to the patient. The development of clinical trials is underway to use 4DCT-ventilation imaging to spare functional lung in patients undergoing radiotherapy. The purpose of this work was to perform a virtual trial using retrospective data to develop the practical aspects of a 4DCT-ventilation functional avoidance clinical trial. METHODS: The study included 96 stage III lung cancer patients. A 4DCT-ventilation map was calculated using the patient's 4DCT-imaging, deformable registration, and a density-change-based algorithm. Clinical trial inclusion assessment used quantitative and qualitative metrics based on the patient's spatial ventilation profile. Clinical and functional plans were generated for 25 patients. The functional plan aimed to reduce dose to functional lung while meeting standard target and critical structure constraints. Standard and dose-function metrics were compared between the clinical and functional plans. RESULTS: Our data showed that 69% and 59% of stage III patients have regional variability in function based on qualitative and quantitative metrics, respectively. Functional planning demonstrated an average reduction of 2.8 Gy (maximum 8.2 Gy) in the mean dose to functional lung. CONCLUSIONS: Our work demonstrated that 60-70% of stage III patients would be eligible for functional planning and that a typical functional lung mean dose reduction of 2.8 Gy can be expected relative to standard clinical plans. These findings provide salient data for the development of functional clinical trials.

Practical implementation of quality improvement for high-dose-rate brachytherapy.

PURPOSE: High-dose-rate (HDR) brachytherapy is a high-risk procedure with serious errors reported in the medical literature. Our goal was to develop a quality improvement framework for HDR brachytherapy using a multidisciplinary approach. This work describes the time, personnel, and materials involved in implementation as well as staff-reported safety benefits of quality improvement checklists. METHODS AND MATERIALS: Quality improvement was achieved using a department-wide multidisciplinary approach. Process mapping of the entire HDR program, from initial scheduling through follow-up, was performed. The scope of the project was narrowed to the point of treatment delivery. Two types of multidisciplinary checklists were created: a safety-timeout checklist to ensure safety-critical actions were performed before treatment initiation; and detailed procedure checklists that served as written procedures for physicians, physicists, dosimetrists, and nurses. Implementation was carried out through initial training led by various staff members, creation of visual training guides, piloting and use of checklists for all treatments, and auditing of checklist compliance. RESULTS: Process maps of the entire HDR program were generated and used to guide subsequent changes in the treatment delivery process. A single safety-timeout checklist and the individual procedure checklists were created and used at the time of treatment delivery. The 3-month audit showed that the safety-timeout checklist was used for 100% of treatment fractions. Individual procedure checklists were used for 85% of fractions. All cross-covering physicians and physicists continued to use these checklists 100% of the time. Staff survey results indicated improvements in safety and increased benefits for cross-covering staff. CONCLUSIONS: In using a multidisciplinary approach to quality improvement, process mapping and comprehensive checklists for HDR treatment delivery have been implemented. This has resulted in improved practices that are optimal in our department. This experience can provide others with practical strategies toward implementing such changes in their own facilities.

RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma.

PURPOSE: Radiation Therapy Oncology Group 0417 was a phase II study that explored the safety and efficacy of the addition of bevacizumab to chemoradiation therapy. The safety results have been previously reported. Herein we report the secondary efficacy endpoints of overall survival (OS), locoregional failure (LRF), para-aortic nodal failure (PAF), distant failure (DF), and disease-free survival (DFS). METHODS AND MATERIALS: Eligible patients with bulky Stage IB-IIIB disease were treated with once-weekly cisplatin (40 mg/m2) chemotherapy and standard pelvic radiation therapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for 3 cycles during chemoradiation. For OS, failure was defined as death of any cause and was measured from study entry to date of death. LRF was defined as any failure in the pelvis. PAF was defined as any para-aortic nodal failure. DF was analyzed both including and excluding PAF. DFS was measured from study entry to date of first LRF. DF was measured with or without PAF or death. OS and DFS were estimated by the Kaplan-Meier method, and LRF and DF rates were estimated by the cumulative incidence method. RESULTS: 49 eligible patients from 28 institutions were enrolled between 2006 and 2009. The median follow-up time was 3.8 years (range, 0.8-6.0 years). The surviving patients had a median follow-up time of 3.9 years (range, 2.1-6.0 years). Most patients had tumors of International Federation of Gynecology and Obstetrics Stage IIB (63%), and 80% were squamous. The 3-year OS, DFS, and LRF were 81.3% (95% confidence interval [CI], 67.2%-89.8%), 68.7% (95% CI, 53.5%-79.8%), and 23.2% (95% CI, 11%-35.4%), respectively. The PAF, DF without PAF, and DF with PAF at 3 years were 8.4% (95% CI, 0.4%-16.3%), 14.7% (95% CI, 4.5%-24.9%), and 23.1% (95% CI 11.0%-35.2%), respectively. CONCLUSION: In this study, bevacizumab in combination with standard pelvic chemoradiation therapy for locally advanced cervical cancer showed efficacy results that are promising and may warrant further investigation.

Dosimetric errors during treatment of centrally located lung tumors with stereotactic body radiation therapy: Monte Carlo evaluation of tissue inhomogeneity corrections.

Early experience with stereotactic body radiation therapy (SBRT) of centrally located lung tumors indicated increased rate of high-grade toxicity in the lungs. These clinical results were based on treatment plans that were computed using pencil beam-like algorithms and without tissue inhomogeneity corrections. In this study, we evaluated the dosimetric errors in plans with and without inhomogeneity corrections and with planning target volumes (PTVs) that were within the zone of the proximal bronchial tree (BT). For 10 patients, the PTV, lungs, and sections of the BT either inside or within 2cm of the PTV were delineated. Two treatment plans were generated for each patient using the following dose-calculation methods: (1) pencil beam (PB) algorithm without inhomogeneity correction (IC) (PB - IC) and (2) PB with inhomogeneity correction (PB + IC). Both plans had identical beam geometry but different beam segment shapes and monitor units (MU) to achieve similar conformal dose coverage of PTV. To obtain the baseline dose distributions, each plan was recalculated using a Monte Carlo (MC) algorithm by keeping MUs the same in the respective plans. The median maximum dose to the proximal BT and PTV dose coverage in the PB + IC plans were overestimated by 8% and 11%, respectively. However, the median maximum dose to the proximal BT and PTV dose coverage in PB - IC plans were underestimated by 15% and 9%. Similar trends were observed in low-dose regions of the lung within the irradiated volume. Our study indicates that dosimetric bias introduced by unit tissue density plans cannot be characterized as underestimation or overestimation of dose without taking the tumor location into account. This issue should be considered when analyzing clinical toxicity data from early lung SBRT trials that utilized unit tissue density for dose calculations.

Rotational setup errors in pediatric stereotactic radiation therapy.

PURPOSE: Stereotactic radiation therapy (SRT) is an increasingly commonly used technique in children. The use of image guidance increases the ability to accurately position patients. With our robotic couch, rotational errors that can be corrected are limited to approximately 3 degrees. Given this limitation, we reviewed the rotational setup errors in our pediatric brain tumor population. METHODS AND MATERIALS: We reviewed the rotational corrections for all pediatric (age ≤21 years old) patients treated at our facility from 2009 to 2011. We compared children <5 years old treated to children between 5 and 21 years old (≥5 years old). Also, we analyzed the effect of steroid use and trends in rotational errors over the treatment period in each age group. RESULTS: The mean pitch, roll, and yaw rotational setup errors for younger children are -0.70 ± 2.60 degrees, -0.06 ± 1.89 degrees, and 0.69 ± 2.42 degrees, respectively; for children ≥5 years old, they are 0.46 ± 2.09 degrees, -0.06 ± 1.89 degrees, and 0.69 ± 2.42 degrees, respectively. The mean pitch corrections are larger for children <5 years old (P < .001) and the variance of the pitch, roll, and yaw corrections are all larger for children <5 years old (P < .001). The frequency of rotational errors above 3 degrees for pitch, roll, and yaw is 21.7%, 10.6%, and 20.9% for children <5 years old, and 15.6%, 2.1%, and 13.8% for children ≥5 years old. In both age groups, pitch and roll corrections were larger for children treated with steroids. CONCLUSIONS: Rotational errors in our pediatric population occur more frequently than previously reported, and are more common in younger children and in children treated with steroids. These rotational set up errors may not be fully correctable due to mechanical and safety limitations. We have altered our planning and treatment process to better account for rotational errors in children receiving SRT.

Regional normal lung tissue density changes in patients treated with stereotactic body radiation therapy for lung tumors.

PURPOSE: To describe regional lung tissue density changes in normal lung tissue of patients with primary and metastatic lung tumors who received stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: A total of 179 post-SBRT follow-up computed tomography (CT) scans of 62 patients who received SBRT between 2003 and 2009 were studied. Median prescription dose was 54 Gy (range, 30-60 Gy) in 3 to 5 fractions. SBRT-induced lung density changes on post-SBRT follow-up CT were evaluated at approximately 3, 6, 12, 18, 24, and 30 months after treatment. Dose-response curves (DRC) were generated for SBRT-induced lung damage by averaging CT number (HU) changes for regions of the lungs receiving the same dose at 5-Gy intervals. RESULTS: For all follow-up interval periods, CT numbers linearly increased with dose until 35 Gy and were constant thereafter. For 3, 18, 24, and 30 months, the rate of relative electron density increase with dose was approximately 0.24% per Gy. At 6 months, the rate was also similar below 20 Gy but then rose to 0.6% per Gy above this threshold. After 6 months, DRCs were mostly time-independent. When split between patients treated with 3 fractions of 12 to 20 Gy (median, 20 Gy; average tumor volume, 12±16 cm3) and with >3 fractions of 6 to 12.5 Gy (median, 9 Gy; average tumor volume, 30±40 cm3), DRCs differed significantly. In both cases, CT changes at 3, 18, 24, and 30 months were identical to those of the population DRC; however, patients who received >3 fractions showed 6-month CT changes that were more than twice those for the group that received 3 fractions. CONCLUSIONS: This analysis of SBRT-induced normal lung density changes indicates that lung normal tissue has more pronounced self-limited acute effects than late effects. Differences in acute CT changes following treatments in 3 fractions were considerably less than for treatments in >3 fractions.

Phase II trial of hypofractionated IMRT with temozolomide for patients with newly diagnosed glioblastoma multiforme.

PURPOSE: To report toxicity and overall survival (OS) in patients with newly diagnosed glioblastoma multiforme (GBM) treated with hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent and adjuvant temozolomide (TMZ). METHODS AND MATERIALS: Patients with newly diagnosed GBM after biopsy or resection and with adequate performance status and organ or bone marrow function were eligible for this study. Patients received postoperative hypo-IMRT to the surgical cavity and residual tumor seen on T1-weighted brain MRI with a 5-mm margin to a total dose of 60 Gy in 10 fractions (6 Gy/fraction) and to the T2 abnormality on T2-weighted MRI with 5-mm margin to 30 Gy in 10 fractions (3 Gy/fraction). Concurrent TMZ was given at 75 mg/m(2)/day for 28 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Toxicities were defined using Common Terminology Criteria for Adverse Events version 3.0. RESULTS: Twenty-four patients were treated, consisting of 14 men, 10 women; a median age of 60.5 years old (range, 27-77 years); and a median Karnofsky performance score of 80 (range, 60-90). All patients received hypo-IMRT and concurrent TMZ according to protocol, except for 2 patients who received only 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 6.5 (range, 0-14).With a median follow-up of 14.8 months (range, 2.7-34.2 months) for all patients and a minimum follow-up of 20.6 months for living patients, no instances of grade 3 or higher nonhematologic toxicity were observed. The median OS was 16.6 months (range, 4.1-35.9 months). Six patients underwent repeated surgery for suspected tumor recurrence; necrosis was found in 50% to 100% of the resected specimens. CONCLUSION: In selected GBM patients, 60 Gy hypo-IMRT delivered in 6-Gy fractions over 2 weeks with concurrent and adjuvant TMZ is safe. OS in this small cohort of patients was comparable to that treated with current standard of care therapy.

A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma: preliminary results of RTOG 0417.

PURPOSE: Concurrent cisplatin-based chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer. RTOG 0417 was a Phase II study exploring the safety and efficacy of the addition of bevacizumab to standard CRT. METHODS AND MATERIALS: Eligible patients with bulky tumors (Stage IB-IIIB) were treated with once-weekly cisplatin (40 mg/m(2)) chemotherapy and standard pelvic radiotherapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for three cycles. Treatment-related serious adverse event (SAE) and other adverse event (AE) rates within the first 90 days from treatment start were determined. Treatment-related SAEs were defined as any Grade ≥ 4 vaginal bleeding or thrombotic event or Grade ≥ 3 arterial event, gastrointestinal (GI) bleeding, or bowel/bladder perforation, or any Grade 5 treatment-related death. Treatment-related AEs included all SAEs and Grade 3 or 4 GI toxicity persisting for >2 weeks despite medical intervention, Grade 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia, Grade 3 or 4 other hematologic toxicity, and Grade 3 or 4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs. All AEs were scored using the National Cancer Institute Common Terminology Criteria (CTCAE) v 3.0 (MedDRA version 6.0). RESULTS: A total of 60 patients from 28 institutions were enrolled between 2006 and 2009, and of these, 49 patients were evaluable. The median follow-up was 12.4 months (range, 4.6-31.4 months).The median age was 45 years (range, 22-80 years). Most patients had FIGO Stage IIB (63%) and were of Zubrod performance status of 0 (67%). 80% of cases were squamous. There were no treatment-related SAEs. There were 15 (31%) protocol-specified treatment-related AEs within 90 days of treatment start; the most common were hematologic (12/15; 80%). 18 (37%) occurred during treatment or follow-up at any time. 37 of the 49 patients (76%) had cisplatin and bevacizumab administered per protocol, and 46 of the 49 (94%) had both external beam and brachytherapy administered per protocol or with acceptable variation. CONCLUSION: Bevacizumab in addition to standard pelvic chemoradiotherapy for locally advanced cervical cancer is feasible and safe with respect to the protocol-specified treatment-related SAEs and AEs.

Phase I trial of hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy for patients with newly diagnosed glioblastoma multiforme.

PURPOSE: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. METHODS AND MATERIALS: Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m(2)/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m(2)/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. RESULTS: A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis. CONCLUSIONS: The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with concurrent and adjuvant TMZ is tolerable in selected patients with a T(1)-weighted enhancing tumor <6 cm.

Dosimetric comparison between 3DCRT and IMRT using different multileaf collimators in the treatment of brain tumors.

We investigated the differences between 3-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT), and the impact of collimator leaf-width on IMRT plans for the treatment of nonspherical brain tumors. Eight patients treated by 3DCRT with Novalis were selected. We developed 3 IMRT plans with different multileaf collimators (Novalis m3, Varian MLC-120, and Varian MLC-80) with the same treatment margins, number of beams, and gantry positions as in the 3DCRT treatment plans. Treatment planning utilized the BrainLAB treatment planning system. For each patient, the dose constraints and optimization parameters remained identical for all plans. The heterogeneity index, the percentage target coverage, critical structures, and normal tissue volumes receiving 50% of the prescription dose were calculated to compare the dosimetric difference. Equivalent uniform dose (EUD) and tumor control probability (TCP) were also introduced to evaluate the radiobiological effect for different plans. We found that IMRT significantly improved the target dose homogeneity compared to the 3DCRT. However, IMRT showed the same radiobiological effect as 3DCRT. For the brain tumors adjacent to (or partially overlapping with) critical structures, IMRT dramatically spared the volume of the critical structures to be irradiated. In IMRT plans, the smaller collimator leaf width could reduce the volume of critical structures irradiated to the 50% level for those partially overlapping with the brain tumors. For relatively large and spherical brain tumors, the smaller collimator leaf widths give no significant benefit.