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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. Significance Online 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., (© 2023 Institute of Physics and Engineering in Medicine.)

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., (© 2021 Institute of Physics and Engineering in Medicine.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 (OA W ), and daily online adaptation (OA D ). 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 OA D mitigated random delivery errors more effectively than OA W on a fraction per fraction basis, both OA W and OA D achieved the clinical goals for all ten patients, while BP failed for six cases. In the high-risk CTV, accumulated values of D 98% ranged between 97.15% and 99.73% of the prescription dose for OA D , with a median of 98.07%. For OA W , 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 OA W could be used as an alternative approach to OA D for most patients in order to reduce the clinical workload., (© 2021 Institute of Physics and Engineering in Medicine.)

Adaptive proton therapy (APT) is a promising approach for the treatment of head and neck cancers. One crucial element of APT is daily volumetric imaging of the patient in the treatment position. Such data can be acquired with cone-beam computed tomography (CBCT), although scatter artifacts make uncorrected CBCT images unsuitable for proton therapy dose calculation. The purpose of this work is to evaluate the performance of a U-shape deep convolutive neural network (U-Net) to perform projection-based scatter correction and enable fast and accurate dose calculation on CBCT images in the context of head and neck APT. CBCT projections are simulated for a cohort of 48 head and neck patients using a GPU accelerated Monte Carlo (MC) code . A U-Net is trained to reproduce MC projection-based scatter correction from raw projections. The accuracy of the scatter correction is experimentally evaluated using CT and CBCT images of an anthropomorphic head phantom. The potential of the method for head and neck APT is assessed by comparing proton therapy dose distributions calculated on scatter-free, uncorrected and scatter-corrected CBCT images. Finally, dose calculation accuracy is estimated in experimental patient images using a previously validated empirical scatter correction as reference. The mean and mean absolute HU differences between scatter-free and scatter-corrected images are -0.8 and 13.4 HU, compared to -28.6 and 69.6 HU for the uncorrected images. In the head phantom, the root-mean square difference of proton ranges calculated in the reference CT and corrected CBCT is 0.73 mm. The average 2%/2 mm gamma pass rate for proton therapy plans optimized in the scatter free images and re-calculated in the scatter-corrected ones is 98.89%. In experimental CBCT patient images, a 3%/3 mm passing rate of 98.72% is achieved between the proposed method and the reference one. All CBCT projection volume could be corrected in less than 5 seconds., (© 2020 Institute of Physics and Engineering in Medicine.)

Background and Purpose: To compare time-dependent changes in lung parenchyma of early-stage non-small cell lung carcinoma (NSCLC) patients after stereotactic body radiation therapy with protons (SBPT) or photons (SBRT)., Materials and Method: We retrospectively identified NSCLC patients treated with SBPT and matched each one with a SBRT patient by patient, tumor, and treatment characteristics. Lung parenchyma on serial post-treatment chest computer tomography (CT) scans was deformably registered with the treatment plan to analyze lung density changes as function of dose, quantified by Houndsfield Unit (HU)/Gy. A thoracic radiologist also evaluated the CTs using an established grading system., Results: We matched 23 SBPT/SBRT pairs, including 5 patients treated with both modalities (internally matched cohort). Normal lung response following SBPT significantly increased in the early time period (CTs acquired <6 months, median 3 months) post-treatment, and then did not change significantly in the later time period (CTs acquired 6-14 months, median 9 months). For SBRT, the normal lung response was similar to SBPT in the early time period, but then increased significantly from the early to the late time period (p = 0.007). These differences were most pronounced in sensitive (response >6 HU/Gy) patients and in the internally matched cohort. However, there was no significant difference in the maximum observed response in the entire cohort over all time periods, median 3.4 [IQR, 1.0-5.4] HU/Gy (SBPT) versus 2.5 [1.6-5.2] HU/Gy (SBRT). Qualitative radiological evaluation was highly correlated with the quantitative analysis (p < 0.0001)., Conclusion: While there was no significant difference in maximum response after SBPT versus SBRT, dose-defined lung inflammation occurred earlier after proton irradiation. Further investigation is warranted into the mechanisms of inflammation and therapeutic consequences after proton versus photon irradiation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In proton therapy, range uncertainties induced by the conversion from x-ray CT (xCT) Hounsfield units (HU) to relative stopping power (RSP) compromise the precision of dose delivery. To reduce range uncertainties induced by HU-converted RSPs, this study investigates optimizing the RSP of individual voxels in xCT iteratively based on multi-projection proton radiography (pRG) acquired using a single amorphous silicon flat panel imager. Time-resolved dose rate functions (DRF) were measured by the imager placed downstream of a test phantom consisting of tissue substitute materials. Water equivalent path lengths (WEPL) in the pRG were derived. By rotating the phantom, multiple pRG projections were acquired at angles from 0 to 358° with an increment of 2°. X-ray CT of the phantom was acquired and co-registered with the pRG acquisition coordinates. RSPs of individual xCT voxels were optimized iteratively by minimizing the difference between the measured WEPLs and the calculated WEPLs by ray tracing with HU-converted RSPs. Pixels in pRGs that exhibited severe proton range mixing were rejected for the optimization. Tikhonov regularization was applied under the assumption that HU-converted RSPs are inaccurate, but the inaccuracy is within a few percent. While ~50% of WEPL pixels were rejected due to severe range mixing in pRG, RSPs of  >90% CT voxels could still be optimized if multiple pRG projections, e.g.  ⩾12, around the phantom are utilized. For tissue substitute materials in a cylindrical phantom, percentage errors of RSPs were reduced from a range of  -8% to  +4% to be within  ±2%. Further optimization, achieved by implementing a material-specific regularization parameter, reduced percent errors to be within  ±0.5%. This study demonstrates the concept of optimizing RSPs of individual CT voxels with multi-projection pRGs acquired by a single flat panel imager, which could be further explored and implemented in proton therapy to reduce range uncertainties.

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 D mean change was +0.4% for GTV and +0.3% for clinical target volume. Median change in the maximum dose D max 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., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

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 R 80 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.

For proton therapy, an accurate conversion of CT HU to relative stopping power (RSP) is essential. Validation of the conversion based on real tissue samples is more direct than the current practice solely based on tissue substitutes and can potentially address variations over the population. Based on a novel dose extinction method, we measured water equivalent path lengths (WEPL) on animal tissue samples to evaluate the accuracy of CT HU to RSP conversion and potential variations over a population. A broad proton beam delivered a spread out Bragg peak to the samples sandwiched between a water tank and a 2D ion-chamber detector. WEPLs of the samples were determined from the transmission dose profiles measured as a function of the water level in the tank. Tissue substitute inserts and Lucite blocks with known WEPLs were used to validate the accuracy. A large number of real tissue samples were measured. Variations of WEPL over different batches of tissue samples were also investigated. The measured WEPLs were compared with those computed from CT scans with the Stoichiometric calibration method. WEPLs were determined within  ±0.5% percentage deviation (% std/mean) and  ±0.5% error for most of the tissue surrogate inserts and the calibration blocks. For biological tissue samples, percentage deviations were within  ±0.3%. No considerable difference (<1%) in WEPL was observed for the same type of tissue from different sources. The differences between measured WEPLs and those calculated from CT were within 1%, except for some bony tissues. Depending on the sample size, each dose extinction measurement took around 5 min to produce ~1000 WEPL values to be compared with calculations. This dose extinction system measures WEPL efficiently and accurately, which allows the validation of CT HU to RSP conversions based on the WEPL measured for a large number of samples and real tissues.

Purpose: To quantify and compare the impact of interfractional setup and anatomic variations on proton therapy (PT) and intensity modulated radiation therapy (IMRT) for prostate cancer., Methods and Materials: Twenty patients with low-risk or intermediate-risk prostate cancer randomized to receive passive-scattering PT (n=10) and IMRT (n=10) were selected. For both modalities, clinical treatment plans included 50.4 Gy(RBE) to prostate and proximal seminal vesicles, and prostate-only boost to 79.2 Gy(RBE) in 1.8 Gy(RBE) per fraction. Implanted fiducials were used for prostate localization and endorectal balloons were used for immobilization. Patients in PT and IMRT arms received weekly computed tomography (CT) and cone beam CT (CBCT) scans, respectively. The planned dose was recalculated on each weekly image, scaled, and mapped onto the planning CT using deformable registration. The resulting accumulated dose distribution over the entire treatment course was compared with the planned dose using dose-volume histogram (DVH) and γ analysis., Results: The target conformity index remained acceptable after accumulation. The largest decrease in the average prostate D98 was 2.2 and 0.7 Gy for PT and IMRT, respectively. On average, the mean dose to bladder increased by 3.26 ± 7.51 Gy and 1.97 ± 6.84 Gy for PT and IMRT, respectively. These values were 0.74 ± 2.37 and 0.56 ± 1.90 for rectum. Differences between changes in DVH indices were not statistically significant between modalities. All volume indices remained within the protocol tolerances after accumulation. The average pass rate for the γ analysis, assuming tolerances of 3 mm and 3%, for clinical target volume, bladder, rectum, and whole patient for PT/IMRT were 100/100, 92.6/99, 99.2/100, and 97.2/99.4, respectively., Conclusion: The differences in target coverage and organs at risk dose deviations for PT and IMRT were not statistically significant under the guidelines of this protocol., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To demonstrate the feasibility of proton dose calculation on scatter-corrected cone-beam computed tomographic (CBCT) images for the purpose of adaptive proton therapy., Methods: CBCT projection images were acquired from anthropomorphic phantoms and a prostate patient using an on-board imaging system of an Elekta infinity linear accelerator. Two previously introduced techniques were used to correct the scattered x-rays in the raw projection images: uniform scatter correction (CBCTus) and a priori CT-based scatter correction (CBCTap). CBCT images were reconstructed using a standard FDK algorithm and GPU-based reconstruction toolkit. Soft tissue ROI-based HU shifting was used to improve HU accuracy of the uncorrected CBCT images and CBCTus, while no HU change was applied to the CBCTap. The degree of equivalence of the corrected CBCT images with respect to the reference CT image (CTref) was evaluated by using angular profiles of water equivalent path length (WEPL) and passively scattered proton treatment plans. The CBCTap was further evaluated in more realistic scenarios such as rectal filling and weight loss to assess the effect of mismatched prior information on the corrected images., Results: The uncorrected CBCT and CBCTus images demonstrated substantial WEPL discrepancies (7.3 ± 5.3 mm and 11.1 ± 6.6 mm, respectively) with respect to the CTref, while the CBCTap images showed substantially reduced WEPL errors (2.4 ± 2.0 mm). Similarly, the CBCTap-based treatment plans demonstrated a high pass rate (96.0% ± 2.5% in 2 mm/2% criteria) in a 3D gamma analysis., Conclusions: A priori CT-based scatter correction technique was shown to be promising for adaptive proton therapy, as it achieved equivalent proton dose distributions and water equivalent path lengths compared to those of a reference CT in a selection of anthropomorphic phantoms.

Purpose: The α-to-β (α/β) ratio for prostate tumor is likely lower than that for the surrounding normal organs, such as rectum and bladder (≈ 3 Gy). As a result, hypofractionation is expected to improve the therapeutic ratio in prostate radiation therapy. However, with the use of fewer, larger fractions, the accuracy of treatment dose delivery becomes more influenced by the physical uncertainties resulting from motion and radiobiological uncertainties in the α/β ratio of the prostate tumor. The purpose of this study is to evaluate the impact of interfractional motion on treatment dose delivery within the likely range of the tumor α/β ratio., Methods: Serial CT images acquired at simulation and daily treatment for three prostate patients were studied retrospectively. A conventional 3D-conformal proton plan was created for each patient, delivering 25 fractions of 2 Gy to ITV1 (internal target volume, expanded from the prostate and clinically involved seminal vesicles) followed by 14 fractions to ITV2 (expanded from the prostate). The plans were renormalized for a series of hypofractionated protocols of between five and 28 fractions. The fractional doses were computed on daily CT and were mapped onto simulation CT using deformable registration. In each course, the doses from the fractions with the lowest D97% of the ITV2 were summed to approximate the lower limit (worst case) of target coverage. The uncertainty in dose and coverage was estimated as the deviation of the worst case from the nominal plan., Results: For treatments in 28 to five fractions, the uncertainty arising from interfractional motion ranged from ≈ 1% to 4% for V100% and ≈ 2% to 6% for D100% of the ITV2. The uncertainties in V95% and D95% were both minimal (<1%) for all protocols. For tumors with a low α/β of 1.0 Gy, the treatment in five fractions could deliver an additional 21.0 and 17.4 GyEQD2 to 95% and 100% of the ITV2, respectively, compared to that in 28 fractions. This advantage disappeared for tumors with α/β > 2.5 Gy, assuming the worst case for interfractional motion., Conclusions: In hypofractionated proton therapy for prostate cancer, the dosimetric uncertainties due to interfractional motion were minimal for the ITV2 coverage at 95% isodose level and the dose received by 95% of the ITV2. Although hypofractionation could yield an increase in equivalent dose to the target for tumors with low α/β, the gain was cancelled out by the uncertainty due to interfractional motion for tumors with α/β > 2.5 Gy.

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.

Purpose: In proton therapy, uncertainty in the location of the distal dose edge can lead to cautious treatment plans that reduce the dosimetric advantage of protons. After radiation exposure, vertebral bone marrow undergoes fatty replacement that is visible on magnetic resonance imaging (MRI). This presents an exciting opportunity to observe radiation dose distribution in vivo. We used quantitative spine MRI changes to precisely detect the distal dose edge in proton radiation patients., Methods and Materials: We registered follow-up T1-weighted MRI images to planning computed tomography scans from 10 patients who received proton spine irradiation. A radiation dose-MRI signal intensity curve was created using the lateral beam penumbra in the sacrum. This curve was then used to measure range errors in the lumbar spine., Results: In the lateral penumbra, there was an increase in signal intensity with higher dose throughout the full range of 0-37.5 Gy (RBE). In the distal fall-off region, the beam sometimes appeared to penetrate farther than planned. The mean overshoot in 10 patients was 1.9 mm (95% confidence interval, 0.8-3.1 mm), on the order of the uncertainties inherent to our range verification method., Conclusions: We have demonstrated in vivo proton range verification using posttreatment spine MRI changes. Our analysis suggests the presence of a systematic overshoot of a few millimeters in some proton spine treatments, but the range error does not exceed the uncertainty incorporated into the treatment planning margin. It may be possible to extend our technique to MRI sequences that show early bone marrow changes, enabling adaptive treatment modification., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective. This study describes geometry-based and intensity-based tools for quality assurance (QA) of automatically generated structures for online adaptive radiotherapy, and designs an operator-independent traffic light system that identifies erroneous structure sets. Approach. A cohort of eight head and neck (HN) patients with daily CBCTs was selected for test development. Radiotherapy contours were propagated from planning computed tomography (CT) to daily cone beam CT (CBCT) using deformable image registration. These propagated structures were visually verified for acceptability. For each CBCT, several error scenarios were used to generate what were judged unacceptable structures. Ten additional HN patients with daily CBCTs and different error scenarios were selected for validation. A suite of tests based on image intensity, intensity gradient, and structure geometry was developed using acceptable and unacceptable HN planning structures. Combinations of one test applied to one structure, referred to as structure-test combinations, were selected for inclusion in the QA system based on their discriminatory power. A traffic light system was used to aggregate the structure-test combinations, and the system was evaluated on all fractions of the ten validation HN patients. Results. The QA system distinguished between acceptable and unacceptable fractions with high accuracy, labeling 294/324 acceptable fractions as green or yellow and 19/20 unacceptable fractions as yellow or red. Significance. This study demonstrates a system to supplement manual review of radiotherapy planning structures. Automated QA is performed by aggregating results from multiple intensity- and geometry-based tests. [ABSTRACT FROM AUTHOR]

Simple Summary: The availability of high-quality image guidance and fully integrated online adaptation now allows for an efficient online adaptation for photon treatments. Since proton treatments can deliver a lower dose to healthy tissue, a combination of protons with online adaptation might further reduce side effects. This study compares the calculated side effects for the liver and duodenal toxicity of hypofractionated liver cancer treatments for protons and photons in an adaptive and non-adaptive setting. The results show that the differences between photons and protons are often significant, while the differences between adaptive and non-adaptive treatment schemes are not. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Adaptive proton therapy requires taking images over the course of treatment to correct the plan for anatomy changes. Most workflows assume daily imaging for this purpose. The associated imaging doses can be significant, which may compromise one of the proton therapy aims: minimizing the dose to healthy tissue. Low-dose scanning protocols address this problem. In this paper, we evaluate the influence of low-dose CT protocols on adaptation. We used a head phantom to define the protocols and simulated adaptive treatments of 10 head-and-neck patients with our established adaptation framework. We assessed the influence of lower image quality on the contour propagation and dose calculation. We demonstrated that decreasing the imaging dose by a factor of 40 with respect to our standard CT scanning protocol does not affect the adaptation performance. 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. [ABSTRACT FROM AUTHOR]

Purpose: Hypofractionated radiotherapy of prostate cancer is gaining clinical acceptance given its potential increase in therapeutic ratio and evidence for noninferiority and lack of added late toxicities compared to conventional fractionation. However, concerns have been raised that smaller number of fractions might lead to larger dosimetric influence by interfractional motion. We aim to compare the effect of these variations on hypofractionated pencil beam scanning (PBS) proton therapy and volumetric modulated arc therapy (VMAT) for localized prostate cancer. Methods: Weekly CT images were acquired for 6 patients participating in a randomized clinical trial. PBS plans featuring bilateral (BL) and a combination of lateral and anterior‐oblique beams (AOL), and VMAT plans were created. All patients were treated to a conventional 79.2 Gy total dose in 44 fractions. For this study, hypofractionated dose to the prostate gland was 51.6 Gy in 12 fractions or 36.25 Gy in 5 fractions, and 32.8, and 23.1 Gy to proximal seminal vesicles, respectively. Patients were simulated with endorectal balloons to aid gland immobilization. Three fiducial markers were implanted for setup guidance. All plans were recomputed on the weekly CT images after aligning with the simulation CT. The entire set of 9 CT images was used for dose recalculation for 12‐fraction and only 5 used for the 5‐fraction case. Adaptive range adjustments were applied to anterior‐oblique beams assuming clinical availability of in vivo range verification. Fractional doses were summed using deformable dose accumulation to approximate the delivered dose. Biologically equivalent dose to 2 Gy(EQD2) was calculated assuming α/β of 1.5 Gy for prostate and 3 Gy for bladder and rectum. Results: The median delivered prostate D98 was 0.13/0.14/0.13 Gy(EQD2) smaller than planned for PBS‐BL, 0.13/0.27/0.17 Gy(EQD2) for PBS‐AOL and 0.59/0.66/0.59 Gy(EQD2) for VMAT, for 44/12/5 fractions, respectively. The largest D98 reduction was 1.5 and 3.5 Gy(EQD2) for CTV1 and CTV2, respectively. Target dose degradation was comparable for all fractionation schemes within each modality. The maximum increase in rectum D2 was 0.98 Gy(EQD2) for a 5‐fraction PBS case. Conclusions: The robustness of PBS and VMAT were comparable for all patients for the studied fractionations. The delivered target dose generally remained within clinical tolerance and the deviations were relatively minor for both fractionation schemes. The delivered OAR dose stayed in compliance with the RTOG hypofractionation constraints for all cases. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the feasibility of proton dose calculation on scatter-corrected cone-beam computed tomographic (CBCT) images for the purpose of adaptive proton therapy. Methods: CBCT projection images were acquired from anthropomorphic phantoms and a prostate patient using an on-board imaging system of an Elekta infinity linear accelerator. Two previously introduced techniques were used to correct the scattered x-rays in the raw projection images: uniform scatter correction (CBCTus) and a priori CT-based scatter correction (CBCTap). CBCT images were reconstructed using a standard FDK algorithm and GPU-based reconstruction toolkit. Soft tissue ROI-based HU shifting was used to improve HU accuracy of the uncorrected CBCT images and CBCTus, while no HU change was applied to the CBCTap. The degree of equivalence of the corrected CBCT images with respect to the reference CT image (CTref) was evaluated by using angular profiles of water equivalent path length (WEPL) and passively scattered proton treatment plans. The CBCTap was further evaluated in more realistic scenarios such as rectal filling and weight loss to assess the effect of mismatched prior information on the corrected images. Results: The uncorrected CBCT and CBCTus images demonstrated substantial WEPL discrepancies (7.3±5.3 mm and 11.1±6.6 mm, respectively) with respect to the CTref, while the CBCTap images showed substantially reduced WEPL errors (2.4±2.0 mm). Similarly, the CBCTap-based treatment plans demonstrated a high pass rate (96.0%±2.5% in 2 mm/2% criteria) in a 3D gamma analysis. Conclusions: A priori CT-based scatter correction technique was shown to be promising for adaptive proton therapy, as it achieved equivalent proton dose distributions and water equivalent path lengths compared to those of a reference CT in a selection of anthropomorphic phantoms. [ABSTRACT FROM AUTHOR]