Utility of Noncancerous Chest CT Features for Predicting Overall Survival and Noncancer Death in Patients With Stage I Lung Cancer Treated With Stereotactic Body Radiotherapy.

BACKGROUND. Noncancerous imaging markers can be readily derived from pre-treatment diagnostic and radiotherapy planning chest CT examinations. OBJECTIVE. The purpose of this article was to explore the ability of noncancerous features on chest CT to predict overall survival (OS) and noncancer-related death in patients with stage I lung cancer treated with stereotactic body radiation therapy (SBRT). METHODS. This retrospective study included 282 patients (168 female, 114 male; median age, 75 years) with stage I lung cancer treated with SBRT between January 2009 and June 2017. Pretreatment chest CT was used to quantify coronary artery calcium (CAC) score, pulmonary artery (PA)-to-aorta ratio, emphysema, and body composition in terms of the cross-sectional area and attenuation of skeletal muscle and subcutaneous adipose tissue at the T5, T8, and T10 vertebral levels. Associations of clinical and imaging features with OS were quantified using a multivariable Cox proportional hazards (PH) model. Penalized multivariable Cox PH models to predict OS were constructed using clinical features only and using both clinical and imaging features. The models' discriminatory ability was assessed by constructing time-varying ROC curves and computing AUC at prespecified times. RESULTS. After a median OS of 60.8 months (95% CI, 55.8-68.0), 148 (52.5%) patients had died, including 83 (56.1%) with noncancer deaths. Higher CAC score (11-399: hazard ratio [HR], 1.83 [95% CI, 1.15-2.91], p = .01; ≥ 400: HR, 1.63 [95% CI, 1.01-2.63], p = .04), higher PA-to-aorta ratio (HR, 1.33 [95% CI, 1.16-1.52], p < .001, per 0.1-unit increase), and lower thoracic skeletal muscle index (HR, 0.88 [95% CI, 0.79-0.98], p = .02, per 10-cm2/m2 increase) were independently associated with shorter OS. Discriminatory ability for 5-year OS was greater for the model including clinical and imaging features than for the model including clinical features only (AUC, 0.75 [95% CI, 0.68-0.83] vs 0.61 [95% CI, 0.53-0.70]; p < .01). The model's most important clinical or imaging feature according to mean standardized regression coefficients was the PA-to-aorta ratio. CONCLUSION. In patients undergoing SBRT for stage I lung cancer, higher CAC score, higher PA-to-aorta ratio, and lower thoracic skeletal muscle index independently predicted worse OS. CLINICAL IMPACT. Noncancerous imaging features on chest CT performed before SBRT improve survival prediction compared with clinical features alone.

Impact of aeration change and beam arrangement on the robustness of proton plans.

This study determines the impact of change in aeration in sinonasal cavities on the robustness of passive-scattering proton therapy plans in patients with sinonasal and nasopharyngeal malignancies. Fourteen patients, each with one planning CT and one CT acquired during radiotherapy were studied. Repeat and planning CTs were rigidly aligned and contours were transferred using deformable registration. The amount of air, tumor, and fluid within the cavity containing the tumor were measured on both CTs. The original plans were recalculated on the repeat CT. Dosimetric changes were measured for the targets and critical structures. Median decrease in gross tumor volume (GTV) was 19.8% and correlated with the time of rescan. The median change in air content was 7.1% and correlated with the tumor shrinkage. The median of the mean dose Dmean change was +0.4% for GTV and +0.3% for clinical target volume. Median change in the maximum dose Dmax of the critical structures were as follows: optic chiasm +0.66%, left optic nerve +0.12%, right optic nerve +0.38%, brainstem +0.6%. The dose to the GTV decreased by more than 5% in 1 case, and the dose to critical structure(s) increased by more than 5% in three cases. These four patients had sinonasal cancers and were treated with anterior proton fields that directly transversed through the involved sinus cavities. The change in dose in the replanning was strongly correlated with the change in aeration (P = 0.02). We found that the change in aeration in the vicinity of the target and the arrangement of proton beams affected the robustness of proton plan.

Proton range shift analysis on brain pseudo-CT generated from T1 and T2 MR.

BACKGROUND: In radiotherapy, MR imaging is only used because it has significantly better soft tissue contrast than CT, but it lacks electron density information needed for dose calculation. This work assesses the feasibility of using pseudo-CT (pCT) generated from T1w/T2w MR for proton treatment planning, where proton range comparisons are performed between standard CT and pCT. MATERIAL AND METHODS: MR and CT data from 14 glioblastoma patients were used in this study. The pCT was generated by using conversion libraries obtained from tissue segmentation and anatomical regioning of the T1w/T2w MR. For each patient, a plan consisting of three 18 Gy beams was designed on the pCT, for a total of 42 analyzed beams. The plan was then transferred onto the CT that represented the ground truth. Range shift (RS) between pCT and CT was computed at R80 over 10 slices. The acceptance threshold for RS was according to clinical guidelines of two institutions. A γ-index test was also performed on the total dose for each patient. RESULTS: Mean absolute error and bias for the pCT were 124 ± 10 and -16 ± 26 Hounsfield Units (HU), respectively. The median and interquartile range of RS was 0.5 and 1.4 mm, with highest absolute value being 4.4 mm. Of the 42 beams, 40 showed RS less than the clinical range margin. The two beams with larger RS were both in the cranio-caudal direction and had segmentation errors due to the partial volume effect, leading to misassignment of the HU. CONCLUSIONS: This study showed the feasibility of using T1w and T2w MRI to generate a pCT for proton therapy treatment, thus avoiding the use of a planning CT and allowing better target definition and possibilities for online adaptive therapies. Further improvements of the methodology are still required to improve the conversion from MRI intensities to HUs.

The influence of anisotropy on the clinical target volume of brain tumor patients.

Objective.Current radiotherapy guidelines for glioma target volume definition recommend a uniform margin expansion from the gross tumor volume (GTV) to the clinical target volume (CTV), assuming uniform infiltration in the invaded brain tissue. However, glioma cells migrate preferentially along white matter tracts, suggesting that white matter directionality should be considered in an anisotropic CTV expansion. We investigate two models of anisotropic CTV expansion and evaluate their clinical feasibility.Approach.To incorporate white matter directionality into the CTV, a diffusion tensor imaging (DTI) atlas is used. The DTI atlas consists of water diffusion tensors that are first spatially transformed into local tumor resistance tensors, also known as metric tensors, and secondly fed to a CTV expansion algorithm to generate anisotropic CTVs. Two models of spatial transformation are considered in the first step. The first model assumes that tumor cells experience reduced resistance parallel to the white matter fibers. The second model assumes that the anisotropy of tumor cell resistance is proportional to the anisotropy observed in DTI, with an 'anisotropy weighting parameter' controlling the proportionality. The models are evaluated in a cohort of ten brain tumor patients.Main results.To evaluate the sensitivity of the model, a library of model-generated CTVs was computed by varying the resistance and anisotropy parameters. Our results indicate that the resistance coefficient had the most significant effect on the global shape of the CTV expansion by redistributing the target volume from potentially less involved gray matter to white matter tissue. In addition, the anisotropy weighting parameter proved useful in locally increasing CTV expansion in regions characterized by strong tissue directionality, such as near the corpus callosum.Significance.By incorporating anisotropy into the CTV expansion, this study is a step toward an interactive CTV definition that can assist physicians in incorporating neuroanatomy into a clinically optimized CTV.

Integrating muscle fiber orientation from visible human data into radiotherapy target volumes.

OBJECTIVE: A major challenge in treatment of tumors near skeletal muscle is defining the target volume for suspected tumor invasion into the muscle. This study develops a framework that generates radiation target volumes with muscle fiber orientation directly integrated into their definition. The framework is applied to nineteen sacral tumor patients with suspected infiltration into surrounding muscles. Approach. To compensate for the poor soft-tissue contrast of CT images, muscle fiber orientation is derived from cryo-images of two cadavers from the Human Visible Project (VHP). The approach consists of (a) detecting image gradients in the cadaver images representative of muscle fibers, (b) mapping this information onto the patient image, and (c) embedding the muscle fiber orientation into an expansion method to generate patient-specific clinical target volumes (CTV). The validation tested the consistency of image gradient orientation across VHP subjects for the piriformis, gluteus maximus, paraspinal, gluteus medius, and gluteus minimus muscles. The model robustness was analyzed by comparing CTVs generated using different VHP subjects. The difference in shape between the new CTVs and standard CTV was analyzed for clinical impact. Main results. Good agreement was found between the image gradient orientation across VHP subjects, as the voxel-wise median cosine similarity was at least 0.86 (for the gluteus minimus) and up to 0.98 for the piriformis. The volume and surface similarity between the CTVs generating from different VHP subjects was on average at least 0.95 and 5.13 mm for the Dice Similarity Coefficient and the Hausdorff 95% Percentile Index, showing excellent robustness. Finally, compared to the standard CTV with different margins in muscle and non-muscle tissue, the new CTV margins are reduced in muscle tissue depending on the chosen clinical margins. Significance. This study implements a method to integrate muscle fiber orientation into the target volume without the need for additional imaging.

Association of Sarcopenia With Toxicity-Related Discontinuation of Adjuvant Endocrine Therapy in Women With Early-Stage Hormone Receptor-Positive Breast Cancer.

PURPOSE: Sarcopenia, an age-related decline in muscle mass and physical function, is associated with increased toxicity and worse outcomes in women with breast cancer (BC). Sarcopenia may contribute to toxicity-related early discontinuation of adjuvant endocrine  therapy (aET) in women with hormone receptor-positive (HR+) BC but remains poorly characterized. METHODS AND MATERIALS: This multicenter, retrospective cohort study included consecutive women with stage 0-II HR+ BC who received breast conserving therapy (lumpectomy and radiation therapy) and aET from 2011 to 2017 with a 5-year follow-up. Skeletal muscle index (SMI, cm2/m2) was analyzed using a deep learning model on routine cross-sectional radiation simulation imaging; sarcopenia was dichotomized according to previously validated reports. The primary endpoint was toxicity-related aET discontinuation; logistic regression analysis evaluated associations between SMI/sarcopenia and aET discontinuation. Cox regression analysis evaluated associations with time to aET toxicity, ipsilateral breast tumor recurrence (IBTR), and disease-free survival (DFS). RESULTS: A total of 305 women (median follow-up, 89 months) were included with a median age of 67 years and early-stage BC (12% stage 0, 65% stage I). A total of 60 (20%) women experienced toxicity-related aET discontinuation. Sarcopenia was associated with toxicity-related early discontinuation of aET (odds ratio, 2.18; P = .036) and shorter time to aET toxicity (hazard ratio [HR], 1.62; P = .031). SMI or sarcopenia were not independently associated with IBTR or DFS; toxicity-related aET discontinuation was associated with worse IBTR (HR, 9.47; P = .002) and worse DFS (HR, 4.53; P = .001). CONCLUSIONS: Among women with early-stage HR+ BC who receive adjuvant radiation therapy and hormone therapy, sarcopenia is associated with toxicity-related early discontinuation of aET. Further studies should validate these findings in women who did not receive adjuvant radiation therapy. These high-risk patients may be candidates for aggressive symptom management and/or alternative treatment strategies to improve outcomes.

Evaluating the effect of setup uncertainty reduction and adaptation to geometric changes on normal tissue complication probability using online adaptive head and neck intensity modulated proton therapy.

Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT).Approach.A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism.Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia (mean reductions of 8.25, 5.42 and 5.12 pp respectively). While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone.SignificanceOnline adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC.

Comparing Predicted Toxicities between Hypofractionated Proton and Photon Radiotherapy of Liver Cancer Patients with Different Adaptive Schemes.

With the availability of MRI linacs, online adaptive intensity modulated radiotherapy (IMRT) has become a treatment option for liver cancer patients, often combined with hypofractionation. Intensity modulated proton therapy (IMPT) has the potential to reduce the dose to healthy tissue, but it is particularly sensitive to changes in the beam path and might therefore benefit from online adaptation. This study compares the normal tissue complication probabilities (NTCPs) for liver and duodenal toxicity for adaptive and non-adaptive IMRT and IMPT treatments of liver cancer patients. Adaptive and non-adaptive IMRT and IMPT plans were optimized to 50 Gy (RBE = 1.1 for IMPT) in five fractions for 10 liver cancer patients, using the original MRI linac images and physician-drawn structures. Three liver NTCP models were used to predict radiation-induced liver disease, an increase in albumin-bilirubin level, and a Child-Pugh score increase of more than 2. Additionally, three duodenal NTCP models were used to predict gastric bleeding, gastrointestinal (GI) toxicity with grades >3, and duodenal toxicity grades 2-4. NTCPs were calculated for adaptive and non-adaptive IMRT and IMPT treatments. In general, IMRT showed higher NTCP values than IMPT and the differences were often significant. However, the differences between adaptive and non-adaptive treatment schemes were not significant, indicating that the NTCP benefit of adaptive treatment regimens is expected to be smaller than the expected difference between IMRT and IMPT.

Large anatomical changes in head-and-neck cancers - A dosimetric comparison of online and offline adaptive proton therapy.

Purpose: This work evaluates an online adaptive (OA) workflow for head-and-neck (H&N) intensity-modulated proton therapy (IMPT) and compares it with full offline replanning (FOR) in patients with large anatomical changes. Methods: IMPT treatment plans are created retrospectively for a cohort of eight H&N cancer patients that previously required replanning during the course of treatment due to large anatomical changes. Daily cone-beam CTs (CBCT) are acquired and corrected for scatter, resulting in 253 analyzed fractions. To simulate the FOR workflow, nominal plans are created on the planning-CT and delivered until a repeated-CT is acquired; at this point, a new plan is created on the repeated-CT. To simulate the OA workflow, nominal plans are created on the planning-CT and adapted at each fraction using a simple beamlet weight-tuning technique. Dose distributions are calculated on the CBCTs with Monte Carlo for both delivery methods. The total treatment dose is accumulated on the planning-CT. Results: Daily OA improved target coverage compared to FOR despite using smaller target margins. In the high-risk CTV, the median D98 degradation was 1.1 % and 2.1 % for OA and FOR, respectively. In the low-risk CTV, the same metrics yield 1.3 % and 5.2 % for OA and FOR, respectively. Smaller setup margins of OA reduced the dose to all OARs, which was most relevant for the parotid glands. Conclusion: Daily OA can maintain prescription doses and constraints over the course of fractionated treatment, even in cases of large anatomical changes, reducing the necessity for manual replanning in H&N IMPT.

Operational Ontology for Oncology (O3): A Professional Society-Based, Multistakeholder, Consensus-Driven Informatics Standard Supporting Clinical and Research Use of Real-World Data From Patients Treated for Cancer.

PURPOSE: The ongoing lack of data standardization severely undermines the potential for automated learning from the vast amount of information routinely archived in electronic health records (EHRs), radiation oncology information systems, treatment planning systems, and other cancer care and outcomes databases. We sought to create a standardized ontology for clinical data, social determinants of health, and other radiation oncology concepts and interrelationships. METHODS AND MATERIALS: The American Association of Physicists in Medicine's Big Data Science Committee was initiated in July 2019 to explore common ground from the stakeholders' collective experience of issues that typically compromise the formation of large inter- and intra-institutional databases from EHRs. The Big Data Science Committee adopted an iterative, cyclical approach to engaging stakeholders beyond its membership to optimize the integration of diverse perspectives from the community. RESULTS: We developed the Operational Ontology for Oncology (O3), which identified 42 key elements, 359 attributes, 144 value sets, and 155 relationships ranked in relative importance of clinical significance, likelihood of availability in EHRs, and the ability to modify routine clinical processes to permit aggregation. Recommendations are provided for best use and development of the O3 to 4 constituencies: device manufacturers, centers of clinical care, researchers, and professional societies. CONCLUSIONS: O3 is designed to extend and interoperate with existing global infrastructure and data science standards. The implementation of these recommendations will lower the barriers for aggregation of information that could be used to create large, representative, findable, accessible, interoperable, and reusable data sets to support the scientific objectives of grant programs. The construction of comprehensive "real-world" data sets and application of advanced analytical techniques, including artificial intelligence, holds the potential to revolutionize patient management and improve outcomes by leveraging increased access to information derived from larger, more representative data sets.

Low-Dose Computed Tomography Scanning Protocols for Online Adaptive Proton Therapy of Head-and-Neck Cancers.

PURPOSE: To evaluate the suitability of low-dose CT protocols for online plan adaptation of head-and-neck patients. METHODS: We acquired CT scans of a head phantom with protocols corresponding to CT dose index volume CTDIvol in the range of 4.2-165.9 mGy. The highest value corresponds to the standard protocol used for CT simulations of 10 head-and-neck patients included in the study. The minimum value corresponds to the lowest achievable tube current of the GE Discovery RT scanner used for the study. For each patient and each low-dose protocol, the noise relative to the standard protocol, derived from phantom images, was applied to a virtual CT (vCT). The vCT was obtained from a daily CBCT scan corresponding to the fraction with the largest anatomical changes. We ran an established adaptive workflow twice for each low-dose protocol using a high-quality daily vCT and the corresponding low-dose synthetic vCT. For a relative comparison of the adaptation efficacy, two adapted plans were recalculated in the high-quality vCT and evaluated with the contours obtained through deformable registration of the planning CT. We also evaluated the accuracy of dose calculation in low-dose CT volumes using the standard CT protocol as reference. RESULTS: The maximum differences in D98 between low-dose protocols and the standard protocol for the high-risk and low-risk CTV were found to be 0.6% and 0.3%, respectively. The difference in OAR sparing was up to 3%. The Dice similarity coefficient between propagated contours obtained with low-dose and standard protocols was above 0.982. The mean 2%/2 mm gamma pass rate for the lowest-dose image, using the standard protocol as reference, was found to be 99.99%. CONCLUSION: The differences between low-dose protocols and the standard scanning protocol were marginal. Thus, low-dose CT protocols are suitable for online adaptive proton therapy of head-and-neck cancers. As such, considering scanning protocols used in our clinic, the imaging dose associated with online adaption of head-and-neck cancers treated with protons can be reduced by a factor of 40.

Evaluation of the dosimetric impact of interfractional anatomical variations on prostate proton therapy using daily in-room CT images.

PURPOSE: To quantify interfractional anatomical variations and their dosimetric impact during the course of fractionated proton therapy (PT) of prostate cancer and to assess the robustness of the current treatment planning techniques. METHODS: Simulation and daily in-room CT scans from ten prostate carcinoma patients were analyzed. PT treatment plans (78 Gy in 39 fractions of 2 Gy) were created on the simulation CT, delivering 25 fractions to PTV1 (expanded from prostate and seminal vesicles), followed by 14 boost fractions to PTV2 (expanded from prostate). Plans were subsequently applied to daily CT, with beams aligned to the prostate center in the sagittal plane. For five patients having a sufficiently large daily imaging volume, structure contours were manually drawn, and plans were evaluated for all CT sets. For the other five patients, the plans were evaluated for six selected fractions. The daily CT was matched to the simulation CT through deformable registration. The registration accuracy was validated for each fraction, and the three patients with a large number of accurately registered fractions were used for dose accumulation. RESULTS: In individual fractions, the coverage of the prostate, seminal vesicles, and PTV1 was generally maintained at the corresponding prescription dose. For PTV2, the volume covered by the fractional prescription dose of 2 Gy (i.e., V2) was, on average, reduced by less than 3% compared to the simulation plan. Among the 225 (39 x 5 + 6 x 5) fractions examined, 15 showed a V2 reduction larger than 5%, of which ten were caused by a large variation in rectal gas, and five were due to a prostate shift in the craniocaudal direction. The fractional dose to the anterior rectal wall was found to increase for one patient who had large rectal gas volume in 25 of the 39 fractions, and another who experienced significant prostate volume reduction during the treatment. The fractional bladder dose generally increased with decreasing fullness. In the total accumulated dose for the three patients after excluding a few fractions with inaccurate registration due to a large amount of rectal gas (a condition inconsistent with RTOG protocol), 98.5%, 96.6%, and 98.2% of the PTV2 received the prescription dose of 78 Gy. The V75 and V70 of the anterior rectal wall and bladder both remained within tolerance. CONCLUSIONS: The results confirm that the PT planning techniques and dose constraints used at our institution ensure that target coverage to the prescription dose is maintained in the presence of interfractional anatomical variations. Dose coverage in individual fractions can be compromised, and normal tissue dose increased, due to deviations in the bladder and rectal volume compared to the simulation plans or progressive changes in the prostate volume during the treatment. Deviations from the plan can be reduced with efforts aimed at maintaining consistent daily patient anatomy.

Physics of Particle Beam and Hypofractionated Beam Delivery in NSCLC.

The dosimetric advantages of particle therapy lead to significantly reduced integral dose to normal tissues, making it an attractive treatment option for body sites such as the thorax. With reduced normal tissue dose comes the potential for dose escalation, toxicity reduction, or hypofractionation. While proton and heavy ion therapy have been used extensively for NSCLC, there are challenges in planning and delivery compared with X-ray-based radiation therapy. Particularly, range uncertainties compounded by breathing motion have to be considered. This article summarizes the current state of particle therapy for NSCLC with a specific focus on the impact of dosimetric uncertainties in planning and delivery.

Adaptive proton therapy.

Radiation therapy treatments are typically planned based on a single image set, assuming that the patient's anatomy and its position relative to the delivery system remains constant during the course of treatment. Similarly, the prescription dose assumes constant biological dose-response over the treatment course. However, variations can and do occur on multiple time scales. For treatment sites with significant intra-fractional motion, geometric changes happen over seconds or minutes, while biological considerations change over days or weeks. At an intermediate timescale, geometric changes occur between daily treatment fractions. Adaptive radiation therapy is applied to consider changes in patient anatomy during the course of fractionated treatment delivery. While traditionally adaptation has been done off-line with replanning based on new CT images, online treatment adaptation based on on-board imaging has gained momentum in recent years due to advanced imaging techniques combined with treatment delivery systems. Adaptation is particularly important in proton therapy where small changes in patient anatomy can lead to significant dose perturbations due to the dose conformality and finite range of proton beams. This review summarizes the current state-of-the-art of on-line adaptive proton therapy and identifies areas requiring further research.

A generalized framework for analytic regularization of uniform cubic B-spline displacement fields.

Image registration is an inherently ill-posed problem that lacks the constraints needed for a unique mapping between voxels of the two images being registered. As such, one must regularize the registration to achieve physically meaningful transforms. The regularization penalty is usually a function of derivatives of the displacement-vector field and can be calculated either analytically or numerically. The numerical approach, however, is computationally expensive depending on the image size, and therefore a computationally efficient analytical framework has been developed. Using cubic B-splines as the registration transform, we develop a generalized mathematical framework that supports five distinct regularizers: diffusion, curvature, linear elastic, third-order, and total displacement. We validate our approach by comparing each with its numerical counterpart in terms of accuracy. We also provide benchmarking results showing that the analytic solutions run significantly faster-up to two orders of magnitude-than finite differencing based numerical implementations.

Anatomic changes in head and neck intensity-modulated proton therapy: Comparison between robust optimization and online adaptation.

BACKGROUND/PURPOSE: Setup variations and anatomical changes can severely affect the quality of head and neck intensity-modulated proton therapy (IMPT) treatments. The impact of these changes can be alleviated by increasing the plan's robustness a priori, or by adapting the plan online. This work compares these approaches in the context of head and neck IMPT. MATERIALS/METHODS: A representative cohort of 10 head and neck squamous cell carcinoma (HNSCC) patients with daily cone-beam computed tomography (CBCT) was evaluated. For each patient, three IMPT plans were created: 1- a classical robust optimization (cRO) plan optimized on the planning CT, 2- an anatomical robust optimization (aRO) plan additionally including the two first daily CBCTs and 3- a plan optimized without robustness constraints, but online-adapted (OA) daily, using a constrained spot intensity re-optimization technique only. RESULTS: The cumulative dose following OA fulfilled the clinical objective of both the high-risk and low-risk clinical target volumes (CTV) coverage in all 10 patients, compared to 8 for aRO and 4 for cRO. aRO did not significantly increase the dose to most organs at risk compared to cRO, although the integral dose was higher. OA significantly reduced the integral dose to healthy tissues compared to both robust methods, while providing equivalent or superior target coverage. CONCLUSION: Using a simple spot intensity re-optimization, daily OA can achieve superior target coverage and lower dose to organs at risk than robust optimization methods.

Technical Note: Cumulative dose modeling for organ motion management in MRI-guided radiation therapy.

PURPOSE: To develop a method for continuous online dose accumulation during irradiation in MRI-guided radiation therapy (MRgRT) and to demonstrate its application in evaluating the impact of internal organ motion on cumulative dose. METHODS: An intensity-modulated radiation therapy (IMRT) treatment plan is partitioned into its unique apertures. Dose for each planned aperture is calculated using Monte Carlo dose simulation on each phase of a four-dimensional computed tomography (4D-CT) dataset. Deformable image registration is then performed both (a) between each frame of a cine-MRI acquisition obtained during treatment and a reference frame, and (b) between each volume of the 4D-CT phases and a reference phase. These registrations are used to associate each cine image with a 4D-CT phase. Additionally, for each 4D-CT phase, the deformation vector field (DVF) is used to warp the pre-calculated dose volumes per aperture onto the reference CT dataset. To estimate the dose volume delivered during each frame of the cine-MRI acquisition, we retrieve the pre-calculated warped dose volume for the delivered aperture on the associated 4D-CT phase and adjust it by a rigid translation to account for baseline drift and instances where motion on the cine image exceeds the amplitude observed between 4D-CT phases. RESULTS: The proposed dose accumulation method is retrospectively applied to a liver cancer case previously treated on an MRgRT platform. Cumulative dose estimated for free-breathing and respiration-gated delivery is compared against dose calculated on static anatomy. In this sample case, the target minimum dose and D 98 varied by as much as 5% and 7%, respectively. CONCLUSION: We demonstrate a technique suitable for continuous online dose accumulation during MRgRT. In contrast to other approaches, dose is pre-calculated per aperture and phase and then retrieved based on a mapping scheme between cine MRI and 4D-CT datasets, aiming at reducing the computational burden for potential real-time applications.

Comparison of weekly and daily online adaptation for head and neck intensity-modulated proton therapy.

The high conformality of intensity-modulated proton therapy (IMPT) dose distributions causes treatment plans to be sensitive to geometrical changes during the course of a fractionated treatment. This can be addressed using adaptive proton therapy (APT). One important question in APT is the frequency of adaptations performed during a fractionated treatment, which is related to the question whether plan adaptation has to be done online or offline. The purpose of this work is to investigate the impact of weekly and daily online IMPT plan adaptation on the treatment quality for head and neck patients. A cohort of ten head and neck patients with daily acquired cone-beam CT (CBCT) images was evaluated retrospectively. Dose tracking of the IMPT treatment was performed for three scenarios: base plan with no adaptation (BP), weekly online adaptation (OAW), and daily online adaptation (OAD). Both adaptation schemes used an in-house developed online APT workflow, performing Monte Carlo dose calculations on scatter-corrected CBCTs. IMPT plan adaptation was achieved by only tuning the weights of a subset of beamlets, based on deformable image registration from the planning CT to each CBCT. Although OADmitigated random delivery errors more effectively than OAWon a fraction per fraction basis, both OAWand OADachieved the clinical goals for all ten patients, while BP failed for six cases. In the high-risk CTV, accumulated values ofD98%ranged between 97.15% and 99.73% of the prescription dose for OAD, with a median of 98.07%. For OAW, values between 95.02% and 99.26% were obtained, with a median of 97.61% of the prescription dose. Otherwise, the dose to most organs at risk was similar for all three scenarios. Globally, our results suggest that OAWcould be used as an alternative approach to OADfor most patients in order to reduce the clinical workload.

Variations in tumor size and position due to irregular breathing in 4D-CT: a simulation study.

PURPOSE: To estimate the position and volume errors in 4D-CT caused by irregular breathing. METHODS: A virtual 4D-CT scanner was designed to reproduce axial mode scans with retrospective resorting. This virtual scanner creates an artificial spherical tumor based on the specifications of the user, and recreates images that might be produced by a 4D-CT scanner using a patient breathing waveform. 155 respiratory waveforms of patients were used to test the variability of 4D-CT scans. Each breathing waveform was normalized and scaled to 1, 2, and 3 cm peak-to-peak motion, and artificial tumors with 2 and 4 cm radius were simulated for each scaled waveform. The center of mass and volume of resorted 4D-CT images were calculated and compared to the expected values of center of mass and volume for the artificial tumor. Intrasubject variability was investigated by running the virtual scanner over different subintervals of each patient's breathing waveform. RESULTS: The average error in the center of mass location of an artificial tumor was less than 2 mm standard deviation for 2 cm motion. The corresponding average error in volume was less than 4%. In the worst-case scenarios, a center of mass error of 1.0 cm standard deviation and volume errors of 30%-60% at inhale were found. Systematic errors were observed in a subset of patients due to irregular breathing, and these errors were more pronounced when the tumor volume is smaller. CONCLUSIONS: Irregular breathing during 4D-CT simulation causes systematic errors in volume and center of mass measurements. These errors are small but depend on the tumor size, motion amplitude, and degree of breathing irregularity.

Evaluation and commissioning of a surface based system for respiratory sensing in 4D CT.

The purpose of this study is to assess the temporal and reconstruction accuracy of a surface imaging system, the GateCT under ideal conditions, and compare the device with a commonly used respiratory surrogate: the Varian RPM. A clinical CT scanner, run in cine mode, was used with two optical devices, GateCT and RPM, to detect respiratory motion. A radiation detector, GM-10, triggers the X-ray on/off to GateCT system, while the RPM is directly synchronized with the CT scanner through an electronic connection. Two phantoms were imaged: the first phantom translated on a rigid plate along the anterior-posterior (AP) direction, and was used to assess the temporal synchronization of each optical system with the CT scanner. The second phantom, consisting of five spheres translating 3 cm peak-to-peak in the superior-inferior direction, was used to assess the quality of rebinned images created by GateCT and RPM. Calibration assessment showed a nearly perfect synchronization with the scanner for both the RPM and GateCT systems, thus demonstrating the good performance of the radiation detector. Results for the volume rebinning test showed discrepancies in volumes for the 3D reconstruction (compared to ground truth) of up to 36% for GateCT and up to 40% for RPM. No statistical difference was proven between the two systems in volume sorting. Errors are mainly due to phase detection inaccuracies and to the large motion of the phantom. This feasibility study assessed the consistency of two optical systems in synchronizing the respiratory signal with the image acquisition. A new patient protocol based on both RPM and GateCT will be soon started.