A comprehensive pre-clinical treatment quality assurance program using unique spot patterns for proton pencil beam scanning FLASH radiotherapy.

BACKGROUND: Quality assurance (QA) for ultra-high dose rate (UHDR) irradiation is a crucial aspect in the emerging field of FLASH radiotherapy (FLASH-RT). This innovative treatment approach delivers radiation at UHDR, demanding careful adoption of QA protocols and procedures. A comprehensive understanding of beam properties and dosimetry consistency is vital to ensure the safe and effective delivery of FLASH-RT. PURPOSE: To develop a comprehensive pre-treatment QA program for cyclotron-based proton pencil beam scanning (PBS) FLASH-RT. Establish appropriate tolerances for QA items based on this study's outcomes and TG-224 recommendations. METHODS: A 250 MeV proton spot pattern was designed and implemented using UHDR with a 215nA nozzle beam current. The QA pattern that covers a central uniform field area, various spot spacings, spot delivery modes and scanning directions, and enabling the assessment of absolute, relative and temporal dosimetry QA parameters. A strip ionization chamber array (SICA) and an Advanced Markus chamber were utilized in conjunction with a 2 cm polyethylene slab and a range (R80) verification wedge. The data have been monitored for over 3 months. RESULTS: The relative dosimetries were compliant with TG-224. The variations of temporal dosimetry for scanning speed, spot dwell time, and spot transition time were within ± 1 mm/ms, ± 0.2 ms, and ± 0.2 ms, respectively. While the beam-to-beam absolute output on the same day reached up to 2.14%, the day-to-day variation was as high as 9.69%. High correlation between the absolute dose and dose rate fluctuations were identified. The dose rate of the central 5 × 5 cm2 field exhibited variations within 5% of the baseline value (155 Gy/s) during an experimental session. CONCLUSIONS: A comprehensive QA program for FLASH-RT was developed and effectively assesses the performance of a UHDR delivery system. Establishing tolerances to unify standards and offering direction for future advancements in the evolving FLASH-RT field.

Using patient-specific bolus for pencil beam scanning proton treatment of periorbital disease.

PURPOSE: A unique mantle cell lymphoma case with bilateral periorbital disease unresponsive to chemotherapy and with dosimetry not conducive to electron therapy was treated with pencil beam scanning (PBS) proton therapy. This patient presented treatment planning challenges due to the thin target, immediately adjacent organs at risk (OAR), and nonconformal orbital surface anatomy. Therefore, we developed a patient-specific bolus and hypothesized that it would provide superior setup robustness, dose uniformity and dose conformity. MATERIALS/METHODS: A blue-wax patient-specific bolus was generated from the patient's face contour to conform to his face and eliminate air gaps. A relative stopping power ratio (RSP) of 0.972 was measured for the blue-wax, and the HUs were overridden accordingly in the treatment planning system (TPS). Orthogonal kV images were used for bony alignment and then to ensure positioning of the bolus through fiducial markers attached to the bolus and their contours in TPS. Daily CBCT was used to confirm the position of the bolus in relation to the patient's surface. Dosimetric characteristics were compared between (a) nonbolus, (b) conventional gel bolus and (c) patient-specific bolus plans. An in-house developed workflow for assessment of daily treatment dose based on CBCT images was used to evaluate inter-fraction dose accumulation. RESULTS: The patient was treated to 24 cobalt gray equivalent (CGE) in 2 CGE daily fractions to the bilateral periorbital skin, constraining at least 50% of each lacrimal gland to under 20 Gy. The bolus increased proton beam range by adding 2-3 energy layers of different fields to help achieve better dose uniformity and adequate dose coverage. In contrast to the plan with conventional gel bolus, dose uniformity was significantly improved with patient-specific bolus. The global maximum dose was reduced by 7% (from 116% to 109%). The max and mean doses were reduced by 6.0% and 7.7%, respectively, for bilateral retinas, and 3.0% and 13.9% for bilateral lacrimal glands. The max dose of the lens was reduced by 2.1%. The rigid shape, along with lightweight, and smooth fit to the patient face was well tolerated and reported as "very comfortable" by the patient. The daily position accuracy of the bolus was within 1 mm based on IGRT marker alignment. The daily dose accumulation indicates that the target coverage and OAR doses were highly consistent with the planning intention. CONCLUSION: Our patient-specific blue-wax bolus significantly increased dose uniformity, reduced OAR doses, and maintained consistent setup accuracy compared to conventional bolus. Quality PBS proton treatment for periorbital tumors and similar challenging thin and shallow targets can be achieved using such patient-specific bolus with robustness on both setup and dosimetry.

Re-Irradiation Therapy for Locally Recurrent Head and Neck Cancer: A National Survey of Practice Patterns.

Using a customized survey consisting of two de-identified clinical scenarios with a total of 86 questions, we showed that substantial variability exists regarding recommendations for therapy of recurrent head and neck cancer. For inoperable gross recurrence arising in a previously irradiated field, recommendations were re-irradiation with curative intent (73%), re-irradiation with palliative intent (4%), chemotherapy alone (5%), and referral to tertiary center (18%). After salvage surgery, only 33% recommended adjuvant re-irradiation, with the remainder preferring observation (46%), chemotherapy alone (10%), and referral to tertiary center (11%). Significant differences were observed with respect to dose, fractionation, technique, and systemic therapy recommendations.

Pencil Beam Scanning Proton Bragg Peak Conformal FLASH in Prostate Cancer Stereotactic Body Radiotherapy.

Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT.

Implementation of novel measurement-based patient-specific QA for pencil beam scanning proton FLASH radiotherapy.

BACKGROUND: Several studies have shown pencil beam scanning (PBS) proton therapy is a feasible and safe modality to deliver conformal and ultra-high dose rate (UHDR) FLASH radiation therapy. However, it would be challenging and burdensome to conduct the quality assurance (QA) of the dose rate along with conventional patient-specific QA (psQA). PURPOSE: To demonstrate a novel measurement-based psQA program for UHDR PBS proton transmission FLASH radiotherapy (FLASH-RT) using a high spatiotemporal resolution 2D strip ionization chamber array (SICA). METHODS: The SICA is a newly designed open-air strip-segmented parallel plate ionization chamber, which is capable of measuring spot position and profile through 2 mm-spacing-strip electrodes at a 20 kHz sampling rate (50 µs per event) and has been characterized to exhibit excellent dose and dose rate linearity under UHDR conditions. A SICA-based delivery log was collected for each irradiation containing the measured position, size, dwell time, and delivered MU for each planned spot. Such spot-level information was compared with the corresponding quantities in the treatment planning system (TPS). The dose and dose rate distributions were reconstructed on patient CT using the measured SICA log and compared to the planned values in volume histograms and 3D gamma analysis. Furthermore, the 2D dose and dose rate measurements were compared with the TPS calculations of the same depth. In addition, simulations using different machine-delivery uncertainties were performed, and QA tolerances were deduced. RESULTS: A transmission proton plan of 250 MeV for a lung lesion was planned and measured in a dedicated ProBeam research beamline (Varian Medical System) with a nozzle beam current between 100 to 215 nA. The worst gamma passing rates for dose and dose rate of the 2D SICA measurements (four fields) compared to TPS prediction (3%/3 mm criterion) were 96.6% and 98.8%, respectively, whereas the SICA-log reconstructed 3D dose distribution achieved a gamma passing rate of 99.1% (2%/2 mm criterion) compared to TPS. The deviations between SICA measured log, and TPS were within 0.3 ms for spot dwell time with a mean difference of 0.069 ± 0.11 s, within 0.2 mm for spot position with a mean difference of -0.016 ± 0.03 mm in the x-direction, and -0.036 ± 0.059 mm in the y-direction, and within 3% for delivered spot MUs. Volume histogram metric of dose (D95) and dose rate (V40Gy/s ) showed minimal differences, within less than 1%. CONCLUSIONS: This work is the first to describe and validate an all-in-one measurement-based psQA framework that can fulfill the goals of validating the dose rate accuracy in addition to dosimetric accuracy for proton PBS transmission FLASH-RT. The successful implementation of this novel QA program can provide future clinical practice with more confidence in the FLASH application.

A Universal Range Shifter and Range Compensator Can Enable Proton Pencil Beam Scanning Single-Energy Bragg Peak FLASH-RT Treatment Using Current Commercially Available Proton Systems.

PURPOSE: Transmission beams have been proposed for ultra-high dose (or FLASH) proton planning, limiting the organ sparing potentials of proton therapy. By pulling back the ranges of the highest energy proton beams and compensating proton ranges to adapt to the target distally, the exit dose of proton beams can be eliminated to better protect organs at risk while still preserving FLASH dose rate delivery. METHOD AND MATERIALS: An inverse planning tool was developed to optimize intensity modulated proton therapy using a single-energy layer for FLASH radiation therapy planning. The range pull-backs were calculated to stop single-energy proton beams at the distal edge of the target. The spot map and weights of each field were optimized to achieve a sufficient dose rate using proton beam Bragg peaks. A C-shape target in phantom, along with 6 consecutive lung cancer patients previously treated using proton stereotactic body radiation therapy were planned using this novel Bragg Peak method and also transmission technique. Dosimetry characteristics and 3-dimensional dose rate were investigated. RESULTS: The minimum monitor units (MU) for transmission and Bragg peak plans were 400 MU/spot and 1200 MU/spot, respectively, corresponding to spot peak dose rates of 670 GyRBE (relative biological effectiveness) per second and 1950 GyRBE per second. Bragg peak plans yield a generally comparable target uniformity while significantly reducing dose spillage volume from the low to medium dose level. For all the 6 lung cases delivery of 34 GyRBE in 1 fraction, assessing Radiation Therapy Oncology Group 0915 constraints, the lung V7GyRBE volume was reduced by up to 32% (P = .001) for Bragg peak plans. The transmission plans tended to generate 2.4% higher FLASH dose rate coverage (V40GyRBE/s) versus Bragg peak plans over the major organs at risk. However, Bragg peak plans could also reach the FLASH radiation therapy threshold of V40GyRBE/s using a higher MU/spot and sophisticated dose-rate optimization algorithm. CONCLUSIONS: This first proof-of-concept study has demonstrated this novel method of combining range pull-back and powerful inverse optimization capable of achieving FLASH dose rate based on currently available machine parameters using a single-energy Bragg peak. Similar target coverage and uniformity can be maintained by Bragg peak FLASH plans while substantially improving the sparing of organs at risk compared with transmission plans.

Combining natural and artificial intelligence for robust automatic anatomy segmentation: Application in neck and thorax auto-contouring.

BACKGROUND: Automatic segmentation of 3D objects in computed tomography (CT) is challenging. Current methods, based mainly on artificial intelligence (AI) and end-to-end deep learning (DL) networks, are weak in garnering high-level anatomic information, which leads to compromised efficiency and robustness. This can be overcome by incorporating natural intelligence (NI) into AI methods via computational models of human anatomic knowledge. PURPOSE: We formulate a hybrid intelligence (HI) approach that integrates the complementary strengths of NI and AI for organ segmentation in CT images and illustrate performance in the application of radiation therapy (RT) planning via multisite clinical evaluation. METHODS: The system employs five modules: (i) body region recognition, which automatically trims a given image to a precisely defined target body region; (ii) NI-based automatic anatomy recognition object recognition (AAR-R), which performs object recognition in the trimmed image without DL and outputs a localized fuzzy model for each object; (iii) DL-based recognition (DL-R), which refines the coarse recognition results of AAR-R and outputs a stack of 2D bounding boxes (BBs) for each object; (iv) model morphing (MM), which deforms the AAR-R fuzzy model of each object guided by the BBs output by DL-R; and (v) DL-based delineation (DL-D), which employs the object containment information provided by MM to delineate each object. NI from (ii), AI from (i), (iii), and (v), and their combination from (iv) facilitate the HI system. RESULTS: The HI system was tested on 26 organs in neck and thorax body regions on CT images obtained prospectively from 464 patients in a study involving four RT centers. Data sets from one separate independent institution involving 125 patients were employed in training/model building for each of the two body regions, whereas 104 and 110 data sets from the 4 RT centers were utilized for testing on neck and thorax, respectively. In the testing data sets, 83% of the images had limitations such as streak artifacts, poor contrast, shape distortion, pathology, or implants. The contours output by the HI system were compared to contours drawn in clinical practice at the four RT centers by utilizing an independently established ground-truth set of contours as reference. Three sets of measures were employed: accuracy via Dice coefficient (DC) and Hausdorff boundary distance (HD), subjective clinical acceptability via a blinded reader study, and efficiency by measuring human time saved in contouring by the HI system. Overall, the HI system achieved a mean DC of 0.78 and 0.87 and a mean HD of 2.22 and 4.53 mm for neck and thorax, respectively. It significantly outperformed clinical contouring in accuracy and saved overall 70% of human time over clinical contouring time, whereas acceptability scores varied significantly from site to site for both auto-contours and clinically drawn contours. CONCLUSIONS: The HI system is observed to behave like an expert human in robustness in the contouring task but vastly more efficiently. It seems to use NI help where image information alone will not suffice to decide, first for the correct localization of the object and then for the precise delineation of the boundary.

Patterns of Care for Elderly Patients With Locally Advanced Head and Neck Cancer.

PURPOSE: To compare patterns of care for elderly patients aged ≥70 years with locally advanced head and neck cancer versus those of younger patients treated for the same disease. METHODS AND MATERIALS: The medical records of 421 consecutive patients over the age of 50 years treated at a single institution between April 2011 and June 2016 for stage III/IV squamous cell carcinoma of the head and neck were reviewed. The primary treatment approach was compared using a t test statistic among 3 age cohorts: 50 to 59 years (118 patients); 60 to 69 years (152 patients); and 70 years and older (151 patients). Logistical regression was used to determine variables that influenced the likelihood of receiving surgery versus nonsurgical treatment, as well as radiation alone versus chemoradiation. RESULTS: There was no difference in sex, T stage, N stage, Karnofsky performance status, or the number of chronic comorbid conditions among the 3 age cohorts (P>.05 for all). A greater proportion of elderly patients aged ≥70 years were treated by radiation alone compared with those aged 50 to 59 and 60 to 69 years (44% vs 16% and 24%, P=.01). Increasing age was associated with a greater likelihood of receiving primary nonsurgical versus surgical treatment (odds ratio 1.023, 95% confidence interval 1.004-1.042) and radiation alone compared with chemoradiation (odds ratio 1.054; 95% confidence interval 1.034-1.075). Ten chemotherapy regimens were used concurrently with radiation for patients aged ≥70 years, including carboplatin/paclitaxel (19%), carboplatin/cetuximab (19%), cisplatin (17%), and cetuximab (17%). CONCLUSIONS: Despite similar performance status and comorbidity burden compared with their younger counterparts, patients aged ≥70 years were more commonly treated with less-aggressive strategies, including radiation alone. The variability of concurrent chemotherapy regimens used further suggests that the standard of care remains to be defined for this population.

Quantitative assessment of target delineation variability for thymic cancers: Agreement evaluation of a prospective segmentation challenge.

OBJECTIVES: We sought to quantitatively determine the inter-observer variability of expert radiotherapy target-volume delineation for thymic cancers, as part of a larger effort to develop an expert-consensus contouring atlas. METHODS: A pilot dataset was created consisting of a standardized case presentation with pre- and post-operative DICOM CT image sets from a single patient with Masaoka-Koga Stage III thymoma. Expert thoracic radiation oncologists delineated tumor targets on the pre- and post-operative scans as they would for a definitive and adjuvant case, respectively. Respondents completed a survey including recommended dose prescription and target volume margins for definitive and post-operative scenarios. Inter-observer variability was analyzed quantitatively with Warfield's simultaneous truth, performance level estimation (STAPLE) algorithm and Dice similarity coefficient (DSC). RESULTS: Seven users completed contouring for definitive and adjuvant cases; of these, 5 completed online surveys. Segmentation performance was assessed, with high mean±SD STAPLE-estimated segmentation sensitivity for definitive case GTV and CTV at 0.77 and 0.80, respectively, and post-operative CTV sensitivity of 0.55; all volumes had specificity of ≥0.99. Inter-observer agreement was markedly higher for the definitive target volumes, with mean±SD DSC of 0.88±0.03 and 0.89±0.04 for GTV and CTV respectively, compared to post-op CTV DSC of 0.69±0.06 (Kruskal-Wallis p<0.01. CONCLUSION: Expert agreement for definitive case volumes was exceptionally high, though significantly lower agreement was noted post-operatively. Technique and dose prescription between experts was substantively consistent, and these preliminary results will be utilized to create an expert-consensus contouring atlas to aid the non-expert radiation oncologist in the planning of these challenging, rare tumors.

Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, clinically aggressive cutaneous neuroendocrine neoplasm with a high mortality rate. Though the etiology is not precisely known, Merkel cell polyomavirus DNA has been found recently in a large percentage of MCC tumors. Other suggested risk factors include sun exposure, immunosuppression, and a history of prior malignancy. Work up of patients with MCC most notably includes nodal staging via clinical examination or sentinel lymph node biopsy. The prognosis for most patients with MCC is poor, and the rarity of MCC precludes the prospective, randomized clinical trials necessary to elucidate optimum treatment protocols. Most published data support the use of a multimodality approach centered around surgical excision with negative margins, sentinel lymph node biopsy to establish the presence or absence of nodal metastases, adjuvant radiothearpy to decrease the risk of recurrence, and systemic chemotherapy in the case of widespread disease.

Prospective assessment of an atlas-based intervention combined with real-time software feedback in contouring lymph node levels and organs-at-risk in the head and neck: Quantitative assessment of conformance to expert delineation.

PURPOSE: A number of studies have previously assessed the role of teaching interventions to improve organ-at-risk (OAR) delineation. We present a preliminary study demonstrating the benefit of a combined atlas and real time software-based feedback intervention to aid in contouring of OARs in the head and neck. METHODS AND MATERIALS: The study consisted of a baseline evaluation, a real-time feedback intervention, atlas presentation, and a follow-up evaluation. At baseline evaluation, 8 resident observers contoured 26 OARs on a computed tomography scan without intervention or aid. They then received feedback comparing their contours both statistically and graphically to a set of atlas-based expert contours. Additionally, they received access to an atlas to contour these structures. The resident observers were then asked to contour the same 26 OARs on a separate computed tomography scan with atlas access. In addition, 6 experts (5 radiation oncologists specializing in the head and neck, and 1 neuroradiologist) contoured the 26 OARs on both scans. A simultaneous truth and performance level estimation (STAPLE) composite of the expert contours was used as a gold-standard set for analysis of OAR contouring. RESULTS: Of the 8 resident observers who initially participated in the study, 7 completed both phases of the study. Dice similarity coefficients were calculated for each user-drawn structure relative to the expert STAPLE composite for each structure. Mean dice similarity coefficients across all structures increased between phase 1 and phase 2 for each resident observer, demonstrating a statistically significant improvement in overall OAR-contouring ability (P < .01). Additionally, intervention improved contouring in 16/26 delineated organs-at-risk across resident observers at a statistically significant level (P ≤ .05) including all otic structures and suprahyoid lymph node levels of the head and neck. CONCLUSIONS: Our data suggest that a combined atlas and real-time feedback-based educational intervention detectably improves contouring of OARs in the head and neck.