MRI-guided Radiotherapy (MRgRT) for Treatment of Oligometastases: Review of Clinical Applications and Challenges.

PURPOSE: Early clinical results on the application of magnetic resonance imaging (MRI) coupled with a linear accelerator to deliver Magnetic Resonance-guided Radiation Therapy (MRgRT) have demonstrated feasibility for safe delivery of stereotactic body radiation therapy in treatment of oligometastatic disease. Here, we set out to review the clinical evidence and challenges associated with MRgRT in this setting. METHODS AND MATERIALS: We performed a systematic review of the literature pertaining to clinical experiences and trials on the use of MRgRT primarily for the treatment of oligometastatic cancers. We reviewed the opportunities and challenges associated with the use of MRgRT. RESULTS: Benefits of MRgRT pertaining to superior soft-tissue contrast, real-time imaging and gating, and online adaptive radiation therapy facilitate safe and effective dose escalation to oligometastatic tumors while simultaneously sparing surrounding healthy tissues. Challenges concerning further need for clinical evidence and technical considerations related to planning, delivery, quality assurance of hypofractionated doses, and safety in the MRI environment must be considered. CONCLUSIONS: The promising early indications of safety and effectiveness of MRgRT for stereotactic body radiation therapy-based treatment of oligometastatic disease in multiple treatment locations should lead to further clinical evidence to demonstrate the benefit of this technology.

Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial.

IMPORTANCE: Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. OBJECTIVE: To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. INTERVENTIONS: Chemoradiation and consolidation chemotherapy with or without metformin. MAIN OUTCOMES AND MEASURES: The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02186847.

Clinical utility of Gafchromic film in an MRI-guided linear accelerator.

BACKGROUND: The purpose of this study is to comprehensively evaluate the suitability of Gafchromic EBT3 and EBT-XD film for dosimetric quality assurance in 0.35 T MR-guided radiotherapy. METHODS: A 0.35 T magnetic field strength was utilized to evaluate magnetic field effects on EBT3 and EBT-XD Gafchromic films by studying the effect of film exposure time within the magnetic field using two timing sequences and film not exposed to MR, the effect of magnetic field exposure on the crystalline structure of the film, and the effect of orientation of the film with respect to the bore within the magnetic field. The orientation of the monomer crystal was qualitatively evaluated using scanning electron microscopy (SEM) compared to unirradiated film. Additionally, dosimetric impact was evaluated through measurements of a series of open field irradiations (0.83 × 0.83-cm2 to 19.92 × 19.92-cm2) and patient specific quality assurance measurements. Open fields were compared to planned dose and an independent dosimeter. Film dosimetry was applied to twenty conventional and twenty stereotactic body radiotherapy (SBRT) patient specific quality assurance cases. RESULTS: No visual changes in crystal orientation were observed in any evaluated SEM images nor were any optical density differences observed between films irradiated inside or outside the magnetic field for both EBT3 and EBT-XD film. At small field sizes, the average difference along dose profiles measured in film compared to the same points measured using an independent dosimeter and to predicted treatment planning system values was 1.23% and 1.56%, respectively. For large field sizes, the average differences were 1.91% and 1.21%, respectively. In open field tests, the average gamma pass rates were 99.8% and 97.2%, for 3%/3 mm and 3%/1 mm, respectively. The median (interquartile range) 3%/3 mm gamma pass rates in conventional QA cases were 98.4% (96.3 to 99.2%), and 3%/1 mm in SBRT QA cases were 95.8% (95.0 to 97.3%). CONCLUSIONS: MR exposure at 0.35 T had negligible effects on EBT3 and EBT-XD Gafchromic film. Dosimetric film results were comparable to planned dose, ion chamber and diode measurements.

Adaptive Radiation Therapy (ART) Strategies and Technical Considerations: A State of the ART Review From NRG Oncology.

The integration of adaptive radiation therapy (ART), or modifying the treatment plan during the treatment course, is becoming more widely available in clinical practice. ART offers strong potential for minimizing treatment-related toxicity while escalating or de-escalating target doses based on the dose to organs at risk. Yet, ART workflows add complexity into the radiation therapy planning and delivery process that may introduce additional uncertainties. This work sought to review presently available ART workflows and technological considerations such as image quality, deformable image registration, and dose accumulation. Quality assurance considerations for ART components and minimum recommendations are described. Personnel and workflow efficiency recommendations are provided, as is a summary of currently available clinical evidence supporting the implementation of ART. Finally, to guide future clinical trial protocols, an example ART physician directive and a physics template following standard NRG Oncology protocol is provided.

Evaluation of a magnetic resonance guided linear accelerator for stereotactic radiosurgery treatment.

INTRODUCTION: The purpose of this study was to investigate the systematic localization accuracy, treatment planning capability, and delivery accuracy of an integrated magnetic resonance imaging guided Linear Accelerator (MR-Linac) platform for stereotactic radiosurgery. MATERIALS AND METHODS: The phantom for the end-to-end test comprises three different compartments: a rectangular MR/CT target phantom, a Winston-Lutz cube, and a rectangular MR/CT isocenter phantom. Hidden target tests were performed at gantry angles of 0, 90, 180, and 270 degrees to quantify the systematic accuracy. Five patient plans with a total of eleven lesions were used to evaluate the dosimetric accuracy. Single-isocenter IMRT treatment plans using 10-15 coplanar beams were generated to treat the multiple metastases. RESULTS: The end-to-end localization accuracy of the system was 1.0 ±â€¯0.1 mm. The conformity index, homogeneity index and gradient index of the plans were 1.26 ±â€¯0.22, 1.22 ±â€¯0.10, and 5.38 ±â€¯1.44, respectively. The average absolute point dose difference between measured and calculated dose was 1.64 ±â€¯1.90%, and the mean percentage of points passing the 3%/1 mm gamma criteria was 96.87%. CONCLUSIONS: Our experience demonstrates that excellent plan quality and delivery accuracy was achievable on the MR-Linac for treating multiple brain metastases with a single isocenter.

Technical Note: Evaluation of plastic scintillator detector for small field stereotactic patient-specific quality assurance.

PURPOSE: To evaluate the performance of a commercial plastic scintillator detector (PSD) for small-field stereotactic patient-specific quality assurance (QA) measurements using flattening-filter-free beam. METHODS: A total of 10 spherical targets [volume range: (0.03 cc-2 cc)] were planned with two techniques: (a) dynamic conformal arc (DCA-10 plans) and (b) volumetric modulated arc therapy (VMAT-10 plans). All plans were generated using Varian Eclipse treatment planning system, and AcurosXB v.13 algorithm in 1.0 mm grid size. Additionally, 14 previously treated cranial and spine SRS plans were evaluated [6 DCA, 8 VMAT, volume range: (0.04 cc-119.02 cc)]. Plan modulation was quantified via two metrics: MU per prescription dose (MU/Rx) and Average Leaf Pair Opening (ALPO). QA was performed on the Varian Edge linear accelerator equipped with HDMLC. Three detectors were used: (a) PinPoint ion chamber (PTW; active volume 0.015 cc), (b) Exradin W1 PSD (Standard Imaging; active volume 0.002 cc), and (c) Gafchromic EBT3 film (Ashland). PinPoint chamber and PSD were positioned perpendicular to beam axis in a Lucy phantom (Standard Imaging); films were placed horizontally capturing the coronal plane. RESULTS: PSD, film, and PinPoint chamber measured average differences of 1.00 ± 1.54%, 1.30 ± 1.69%, and -0.66 ± 2.36%, respectively, compared to AcurosXB dose calculation. As the target volume decreased, PinPoint chamber measured lower doses (maximum -5.07% at 0.07 cc target), while PSD and film measured higher doses (2.87% and 2.54% at 0.03 cc target) than AcurosXB. Film agreed with the benchmark detector PSD by an average difference of 0.31 ± 1.20%, but suffered from larger uncertainty; PinPoint chamber underestimated dose by more than 4% for targets smaller than 0.2 cc. Taking PSD as the measurement standard, DCA plans achieved good QA results across all volumes studied, with an average of -0.07 ± 0.89%; for VMAT plans, PSD measured consistently higher dose (1.95 ± 1.36%) than AcurosXB. Correlation study revealed that plan modulation quantified by both MU/Rx and ALPO correlated significantly with QA results. CONCLUSION: Among all three detectors, PSD demonstrated superior performances in plans with small fields and heavy modulation. High consistency and low uncertainty made PSD a suitable detector for clinical routine SRS QA. PinPoint chamber should be avoided for targets smaller than 0.2 cc; film dosimetry can be utilized with careful evaluation of its uncertainty bracket. Compared to PSD measurements, AcurosXB calculation demonstrated high accuracy for nonmodulated small fields. The positive correlation between plan modulation and QA discrepancy calls for our attention for clinical SRS plans with high modulation.

The American Society for Radiation Oncology's 2015 Core Physics Curriculum for Radiation Oncology Residents.

PURPOSE: The American Society for Radiation Oncology (ASTRO) Physics Core Curriculum Subcommittee (PCCSC) has updated the recommended physics curriculum for radiation oncology resident education to improve consistency in teaching, intensity, and subject matter. METHODS AND MATERIALS: The ASTRO PCCSC is composed of physicists and physicians involved in radiation oncology residency education. The PCCSC updated existing sections within the curriculum, created new sections, and attempted to provide additional clinical context to the curricular material through creation of practical clinical experiences. Finally, we reviewed the American Board of Radiology (ABR) blueprint of examination topics for correlation with this curriculum. RESULTS: The new curriculum represents 56 hours of resident physics didactic education, including a 4-hour initial orientation. The committee recommends completion of this curriculum at least twice to assure both timely presentation of material and re-emphasis after clinical experience. In addition, practical clinical physics and treatment planning modules were created as a supplement to the didactic training. Major changes to the curriculum include addition of Fundamental Physics, Stereotactic Radiosurgery/Stereotactic Body Radiation Therapy, and Safety and Incidents sections, and elimination of the Radiopharmaceutical Physics and Dosimetry and Hyperthermia sections. Simulation and Treatment Verification and optional Research and Development in Radiation Oncology sections were also added. A feedback loop was established with the ABR to help assure that the physics component of the ABR radiation oncology initial certification examination remains consistent with this curriculum. CONCLUSIONS: The ASTRO physics core curriculum for radiation oncology residents has been updated in an effort to identify the most important physics topics for preparing residents for careers in radiation oncology, to reflect changes in technology and practice since the publication of previous recommended curricula, and to provide practical training modules in clinical radiation oncology physics and treatment planning. The PCCSC is committed to keeping the curriculum current and consistent with the ABR examination blueprint.

Characteristics of a novel treatment system for linear accelerator-based stereotactic radiosurgery.

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image-guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter-free (FFF) beams for both high definition (HD120) MLC and conical cone-based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end-to-end accuracy tests, have been performed. The end-to-end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone-beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth-dose curves acquired on the new linac-based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond D(max) were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2-1.8 mm (80%-20%) and 1.9-3.8 mm (90%-10%) relative to 10X FFF, which has 1.2-2.2mm and 2.3-5.1mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails-in), oblique, oblique (rails-out), oblique (rails-in) were: -2.0%, -2.5%, -15.6%, -2.5%, -5.0% for 6X FFF and -1.4%, -1.5%, -12.2%, -2.5%, -5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was -0.4 ± 0.2 mm, 0.1± 0.3mm, and 0.0 ± 0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston-Lutz tests over three months are 0.20 ± 0.03 mm and 0.66 ± 0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac-based SRS and SBRT treatment.

Evaluating organ delineation, dose calculation and daily localization in an open-MRI simulation workflow for prostate cancer patients.

BACKGROUND: This study describes initial testing and evaluation of a vertical-field open Magnetic Resonance Imaging (MRI) scanner for the purpose of simulation in radiation therapy for prostate cancer. We have evaluated the clinical workflow of using open MRI as a sole modality for simulation and planning. Relevant results related to MRI alignment (vs. CT) reference dataset with Cone-Beam CT (CBCT) for daily localization are presented. METHODS: Ten patients participated in an IRB approved study utilizing MRI along with CT simulation with the intent of evaluating the MRI-simulation process. Differences in prostate gland volume, seminal vesicles, and penile bulb were assessed with MRI and compared to CT. To evaluate dose calculation accuracy, bulk-density-assignments were mapped onto respective MRI datasets and treated IMRT plans were re-calculated. For image localization purposes, 400 CBCTs were re-evaluated with MRI as the reference dataset and daily shifts compared against CBCT-to-CT registration. Planning margins based on MRI/CBCT shifts were computed using the van Herk formalism. RESULTS: Significant organ contour differences were noted between MRI and CT. Prostate volumes were on average 39.7% (p = 0.002) larger on CT than MRI. No significant difference was found in seminal vesicle volumes (p = 0.454). Penile bulb volumes were 61.1% higher on CT, without statistical significance (p = 0.074). MRI-based dose calculations with assigned bulk densities produced agreement within 1% with heterogeneity corrected CT calculations. The differences in shift positions for the cohort between CBCT-to-CT registration and CBCT-to-MRI registration are -0.15 ± 0.25 cm (anterior-posterior), 0.05 ± 0.19 cm (superior-inferior), and -0.01 ± 0.14 cm (left-right). CONCLUSIONS: This study confirms the potential of using an open-field MRI scanner as primary imaging modality for prostate cancer treatment planning simulation, dose calculations and daily image localization.

Implementation of a novel algorithm for generating synthetic CT images from magnetic resonance imaging data sets for prostate cancer radiation therapy.

PURPOSE: To describe and evaluate a method for generating synthetic computed tomography (synCT) images from magnetic resonance simulation (MR-SIM) data for accurate digitally reconstructed radiograph (DRR) generation and dose calculations in prostate cancer radiation therapy. METHODS AND MATERIALS: A retrospective evaluation was performed in 9 prostate cancer patients who had undergone MR-SIM in addition to CT simulation (CT-SIM). MR-SIM data were used to generate synCT images by using a novel, voxel-based weighted summation approach. A subset of patients was used for weight optimization, and the number of patients to use during optimization was determined. Hounsfield unit (HU) differences between CT-SIM and synCT images were analyzed via mean absolute error (MAE). Original, CT-based treatment plans were mapped onto synCTs. DRRs were generated, and agreement between CT and synCT-generated DRRs was evaluated via Dice similarity coefficient (DSC). Dose was recalculated, and dose-volume metrics and gamma analysis were used to evaluate resulting treatment plans. RESULTS: Full field-of-view synCT MAE across all patients was 74.3 ± 10.9 HU with differences from CTs of 2.0 ± 8.1 HU and 11.9 ± 46.7 HU for soft tissue structures (prostate, bladder, and rectum) and femoral bones, respectively. Calculated DSCs for anterior-posterior and lateral DRRs were 0.90 ± 0.04 and 0.92 ± 0.05, respectively. Differences in D99%, mean dose, and maximum dose to the clinical target volume from CT-SIM dose calculations were 0.75% ± 0.35%, 0.63% ± 0.34%, and 0.54% ± 0.33%, respectively, for synCT-generated plans. Gamma analysis (2%/2 mm dose difference/distance to agreement) revealed pass rates of 99.9% ± 0.1% (range, 99.7%-100%). CONCLUSION: Generated synCTs enabled accurate DRR generation and dose computation for prostate MR-only simulation. Dose recalculated on synCTs agreed well with original planning distributions. Further validation using a larger patient cohort is warranted.

Online correction of catheter movement using CT in high-dose-rate prostate brachytherapy.

PURPOSE: To present a clinical procedure that readjusts catheters to its planned positions based on pretreatment computed tomography (CT) for patients undergoing high-dose-rate (HDR) prostate brachytherapy, and evaluate the magnitude and dosimetric impact of the adjustments. METHODS AND MATERIALS: Patients received a pretreatment verification CT (vCT) before each fraction. The vCT dataset was imported to the treatment-planning system and fused to the planning CT (pCT) by rigid-body registration based on the implanted fiducials within the prostate. Catheter positions in the vCT were then compared with catheter positions in the pCT in a reconstructed plane through each catheter. Any catheter with difference in penetration larger than 3 mm was manually adjusted by a radiation oncologist before treatment. To evaluate treatment quality, the patient's plan was applied to the vCT off-line and dose delivered to prostate and normal structures were compared with their planned value. RESULTS: Forty-four fractions of 13 consecutive patients were treated using this method. Thirty-nine fractions had at least one catheter adjusted before treatment. A total of 651 catheters were assessed, and 194 catheters (30%) were adjusted by an average amount of 5.8 ± 1.9 mm. In eight fractions the prostate D90 would have decreased by more than 10% from the planned value (with a maximum of 32%) if the catheter displacements were not rectified. After the adjustment, the maximum deviation of D90 was 10.6%. The improvement in D90 is 24% per 1 cm of time-averaged adjustment. CONCLUSIONS: Interfraction catheter motion occurs without any particular pattern. Using pretreatment CTs and restoring each catheter to its planned position ensures that the delivered treatment closely matches the treatment plan and therefore enhances the overall quality of the HDR treatment. The procedure can be readily implemented in any clinical setting.

Clinical commissioning and use of the Novalis Tx linear accelerator for SRS and SBRT.

The purpose of this study was to perform comprehensive measurements and testing of a Novalis Tx linear accelerator, and to develop technical guidelines for com-missioning from the time of acceptance testing to the first clinical treatment. The Novalis Tx (NTX) linear accelerator is equipped with, among other features, a high-definition MLC (HD120 MLC) with 2.5 mm central leaves, a 6D robotic couch, an optical guidance positioning system, as well as X-ray-based image guidance tools to provide high accuracy radiation delivery for stereotactic radiosurgery and stereotactic body radiation therapy procedures. We have performed extensive tests for each of the components, and analyzed the clinical data collected in our clinic. We present technical guidelines in this report focusing on methods for: (1) efficient and accurate beam data collection for commissioning treatment planning systems, including small field output measurements conducted using a wide range of detectors; (2) commissioning tests for the HD120 MLC; (3) data collection for the baseline characteristics of the on-board imager (OBI) and ExacTrac X-ray (ETX) image guidance systems in conjunction with the 6D robotic couch; and (4) end-to-end testing of the entire clinical process. Established from our clinical experience thus far, recommendations are provided for accurate and efficient use of the OBI and ETX localization systems for intra- and extracranial treatment sites. Four results are presented. (1) Basic beam data measurements: Our measurements confirmed the necessity of using small detectors for small fields. Total scatter factors varied significantly (30% to approximately 62%) for small field measurements among detectors. Unshielded stereotactic field diode (SFD) overestimated dose by ~ 2% for large field sizes. Ion chambers with active diameters of 6 mm suffered from significant volume averaging. The sharpest profile penumbra was observed for the SFD because of its small active diameter (0.6 mm). (2) MLC commissioning: Winston Lutz test, light/radiation field congruence, and Picket Fence tests were performed and were within criteria established by the relevant task group reports. The measured mean MLC transmission and dynamic leaf gap of 6 MV SRS beam were 1.17% and 0.36 mm, respectively. (3) Baseline characteristics of OBI and ETX: The isocenter localization errors in the left/right, posterior/anterior, and superior/inferior directions were, respectively, -0.2 ± 0.2 mm, -0.8 ± 0.2 mm, and -0.8 ± 0.4 mm for ETX, and 0.5 ± 0.7 mm, 0.6 ± 0.5 mm, and 0.0 ± 0.5 mm for OBI cone-beam computed tomography. The registration angular discrepancy was 0.1 ± 0.2°, and the maximum robotic couch error was 0.2°. (4) End-to-end tests: The measured isocenter dose differences from the planned values were 0.8% and 0.4%, measured respectively by an ion chamber and film. The gamma pass rate, measured by EBT2 film, was 95% (3% DD and 1 mm DTA). Through a systematic series of quantitative commissioning experiments and end-to-end tests and our initial clinical experience, described in this report, we demonstrate that the NTX is a robust system, with the image guidance and MLC requirements to treat a wide variety of sites - in particular for highly accurate delivery of SRS and SBRT-based treatments.

Daily image guidance with cone-beam computed tomography for head-and-neck cancer intensity-modulated radiotherapy: a prospective study.

PURPOSE: To report on a prospective clinical trial of the use of daily kilovoltage cone-beam computed tomography (CBCT) to evaluate the interfraction and residual error motion of patients undergoing intensity-modulated radiotherapy for head-and-neck cancer. METHODS AND MATERIALS: Patients were treated with intensity-modulated radiotherapy with an Elekta linear accelerator using a mounted CBCT scanner. CBCT was performed before every treatment, and translational (but not rotational) corrections were performed. At least once per week, a CBCT scan was obtained after intensity-modulated radiotherapy. Variations were measured in the medial-lateral, superoinferior, and anteroposterior dimensions, as well as in the rotation around these axes. RESULTS: A total of 28 consecutive patients (1,013 CBCT scans) were studied. The average interfraction shift was 1.4 +/- 1.4, 1.7 +/- 1.9, and 1.8 +/- 2.1 mm in the medial-lateral, superoinferior, and anteroposterior dimensions, respectively. The corresponding average residual error shifts were 0.7 +/- 0.8, 0.9 +/- 0.9, and 0.9 +/- 0.9 mm. These data indicate that in the absence of daily CBCT image-guided radiotherapy, a clinical target volume to planning target volume margin of 3.9, 4.1, and 4.9 mm is needed in the medial-lateral, superoinferior, and anteroposterior dimensions, respectively. With daily CBCT, corresponding margins of 1.6, 2.5, and 1.9 mm should be acceptable. Subgroup analyses showed that larynx cancers and/or intratreatment weight loss indicate a need for slightly larger clinical target volume to planning target volume margins. CONCLUSION: The results of our study have shown that image-guided radiotherapy using CBCT for head-and-neck cancer is effective. These data suggest it allows a reduction in the clinical target volume to planning target volume margins by about 50%, which could facilitate future studies of dose escalation and/or improved toxicity reduction. Caution is particularly warranted for cases in which the targets are mobile (e.g., the tongue).