Radiomics for the Prediction of Pathological Complete Response to Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer: A Prospective Observational Trial.

(1) Background: An increasing amount of research has supported the role of radiomics for predicting pathological complete response (pCR) to neoadjuvant chemoradiation treatment (nCRT) in order to provide better management of locally advanced rectal cancer (LARC) patients. However, the lack of validation from prospective trials has hindered the clinical adoption of such studies. The purpose of this study is to validate a radiomics model for pCR assessment in a prospective trial to provide informative insight into radiomics validation. (2) Methods: This study involved a retrospective cohort of 147 consecutive patients for the development/validation of a radiomics model, and a prospective cohort of 77 patients from two institutions to test its generalization. The model was constructed using T2-weighted, diffusion-weighted, and dynamic contrast-enhanced MRI to understand the associations with pCR. The consistency of physicians' evaluations and agreement on pathological complete response prediction were also evaluated, with and without the aid of the radiomics model. (3) Results: The radiomics model outperformed both physicians' visual assessments in the prospective test cohort, with an area under the curve (AUC) of 0.84 (95% confidence interval of 0.70-0.94). With the aid of the radiomics model, a junior physician could achieve comparable performance as a senior oncologist. (4) Conclusion: We have built and validated a radiomics model with pretreatment MRI for pCR prediction of LARC patients undergoing nCRT.

The impact of phantom design and material-dependence on repeatability and reproducibility of CT-based radiomics features.

PURPOSE: To understand the design of radiomics phantom and material-dependence on repeatability and reproducibility of computed tomography (CT) radiomics features. METHODS: A radiomics phantom consisting of various materials with uniformity, textural, and biological components, was constructed. The phantom was scanned with different manufacturer CT scanners and the scans were repeated multiple times on the same scanner with different acquisition settings as kVp, mAs, orientation, field of view (FOV), slice thickness, pitch, reconstruction kernels, and acquisition mode. A total of 72 phantom scans were included. For each scan, 18 different regions of interest (ROI) were contoured and 708 radiomics features were extracted from each ROI via an open source radiomics tool, IBEX. To relate the phantom data to patient data, the radiomics features from different phantom materials were compared with those extracted from 50 patients' images of five disease sites as brain, head-and-neck, breast, liver, and lung cases using box-plots comparison and principal component analysis (PCA). The temporal stability of imaging features was then evaluated with respect to a controlled scenario (test-retest) via the intra-class correlation coefficient (ICC). The reproducibility of radiomics features with respect to different scanners or acquisition settings were further evaluated with concordance correlation coefficients (CCC). RESULTS: Among all phantom materials, the biological component had feature values closest to human tissues, especially for tumors in brain and liver. The textural component showed similar ranges of variation to lung lesions, particularly for cartridges of rice, cereal, and the 3D-printed textural phantom with fine and rough grid. It also showed that certain materials, such as polystyrene foam, plaster, and peanuts, did not have comparable values to human tissue and could be excluded for future phantom design. High repeatability was observed in the test-retest study as indicated by an ICC value of 0.998 ± 0.020. All materials were used for feature stability analysis. For the inter-scanner study, shape-related features were the most-reliable category with 94% of features having CCC ≥ 0.9, while gradient orientation histogram (GOH) were the least-reliable with only 14.6% meeting the criteria. For the intra-scanner study, the reproducibility of CT-based radiomics features showed material-dependence. In general, the instability of radiomics features introduced by kVp, mAs, pitch, acquisition mode, and orientation were relatively mild. However, the homogeneous materials were more vulnerable to those changes compared to materials with textural patterns. Regardless of material compositions, resolution parameters like FOV and slice thickness, could have large impact on feature stability. Switching between standard and bone reconstruction kernels could also result significant changes to feature reproducibility. CONCLUSION: We have built a radiomics phantom using materials that cover a wide span of tumor textures seen in oncological CT images. The designed phantom presents a preliminary opportunity for investigating reproducibility of radiomics features and the reproducibility can be material dependent. Thus, in the radiomics quality assurance design, it is important to choose appropriate materials that can provide a close range of radiomics features to patients with specific disease sites dependency taken into consideration.

Adaptive Radiation Therapy in the Treatment of Lung Cancer: An Overview of the Current State of the Field.

Lung cancer treatment is constantly evolving due to technological advances in the delivery of radiation therapy. Adaptive radiation therapy (ART) allows for modification of a treatment plan with the goal of improving the dose distribution to the patient due to anatomic or physiologic deviations from the initial simulation. The implementation of ART for lung cancer is widely varied with limited consensus on who to adapt, when to adapt, how to adapt, and what the actual benefits of adaptation are. ART for lung cancer presents significant challenges due to the nature of the moving target, tumor shrinkage, and complex dose accumulation because of plan adaptation. This article presents an overview of the current state of the field in ART for lung cancer, specifically, probing topics of: patient selection for the greatest benefit from adaptation, models which predict who and when to adapt plans, best timing for plan adaptation, optimized workflows for implementing ART including alternatives to re-simulation, the best radiation techniques for ART including magnetic resonance guided treatment, algorithms and quality assurance, and challenges and techniques for dose reconstruction. To date, the clinical workflow burden of ART is one of the major reasons limiting its widespread acceptance. However, the growing body of evidence demonstrates overwhelming support for reduced toxicity while improving tumor dose coverage by adapting plans mid-treatment, but this is offset by the limited knowledge about tumor control. Progress made in predictive modeling of on-treatment tumor shrinkage and toxicity, optimizing the timing of adaptation of the plan during the course of treatment, creating optimal workflows to minimize staffing burden, and utilizing deformable image registration represent ways the field is moving toward a more uniform implementation of ART.

Optimization of treatment isocenter location in single-isocenter LINAC-based stereotactic radiosurgery for management of multiple brain metastases.

PURPOSE: Single-isocenter linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) has become a promising treatment technique for the management of multiple brain metastases. Because of the high prescription dose and steep dose gradient, SRS plans are sensitive to geometric errors, resulting in loss of target coverage and suboptimal local tumor control. Current planning techniques rely on adding a uniform and isotropic setup margin to all gross tumor volumes (GTVs) to account for rotational uncertainties. However, this setup margin may be insufficient, since the magnitude of rotational uncertainties varies and is dependent upon the distance between a GTV and the isocenter. In this study, we designed a framework to determine the optimal isocenter of a single-isocenter SRS plan for multiple brain metastases using stochastic optimization to mitigate potential errors resulting from rotational uncertainties. METHODS: Planning target volumes (PTVs), defined as GTVs plus a 1-mm margin following common SRS planning convention, were assumed to be originally treated with a prescription dose and therefore covered by the prescription isodose cloud. The dose distribution, including the prescription isodose, was considered invariant assuming small rotations throughout the study. A stochastic optimization scheme was developed to determine the location of the optimal isocenter, so that the prescription dose coverage of rotated GTVs, equivalent to the intersecting volumes between the rotated GTVs and original PTVs, was maximized for any random small rotations about the isocenter. To evaluate the coverage of GTVs, the expected V 100 % undergoing random rotations was approximated as the sample average V 100 % undergoing a predetermined number of rotations. The expected V 100 % of each individual GTV and total GTVs was then compared between the plans using the optimal isocenter and the center-of-mass (CoM), respectively. RESULTS: Twenty-two patients previously treated for multiple brain metastases in a single institute were included in this retrospective study. Each patient was initially treated for more than three brain metastases (mean: 7.6; range: 3-15) with the average GTV volume of 0.89 cc (range: 0.03-11.78 cc). The optimal isocenter found for each patient was significantly different from the CoM, with the average Euclidean distance between the optimal isocenter and the CoM being 4.36 ± 2.59 cm. The dose coverage to GTVs was also significantly improved (paired t-test; p < 0.001) when the optimal isocenter was used, with the average V 100 % of total GTVs increasing from 87.1% (standard deviation as std: 11.7%; range: 39.9-98.2%) to 94.2% (std: 5.4%; range: 77.7-99.4%). The volume of a GTV was positively correlated with the expected V 100 % regardless of the isocenter used (Spearman coefficient: ρ = 0.66 ; p < 0.001). The distance between a GTV and the isocenter was negatively correlated with the expected V 100 % when the CoM was used ( ρ = - 0.21 ; p = 0.004), however no significant correlation was found when the optimal isocenter was used ( ρ = - 0.11 ; p = 0.137). CONCLUSION: The proposed framework provides an effective approach to determine the optimal isocenter of single-isocenter LINAC-based SRS plans for multiple brain metastases. The implementation of the optimal isocenter results in SRS plans with consistently higher target coverage despite potential rotational uncertainties, and therefore significantly improves SRS plan robustness against random rotational uncertainties.

Dosimetric comparison and biological evaluation of fixed-jaw intensity-modulated radiation therapy for T-shaped esophageal cancer.

BACKGROUND: To evaluate the dosimetric and biological benefits of the fixed-jaw (FJ) intensity-modulated radiation therapy (IMRT) technique for patients with T-shaped esophageal cancer. METHODS: FJ IMRT plans were generated for thirty-five patients and compared with jaw tracking (JT) IMRT, static jaw (SJ) IMRT and JT volumetric modulated arc therapy (VMAT). Dosimetric parameters, tumor control probability (TCP) and normal tissue complication probability (NTCP), monitor units (MUs), delivery time and gamma passing rate, as a measure of dosimetric verification, were compared. The correlation between the length of PTV-C below the upper boundary of lung tissue (PTV-Cinferior) and dosimetric parameters and NTCP of the lung tissue were analyzed. RESULTS: The homogeneity and conformity of the target in the four plans were basically equivalent. When compared to the JT IMRT and SJ IMRT plans, FJ IMRT plan led to a statistically significant improvement in the NTCP and low-middle dosimetric parameters of the lung, and the improvement had a moderately positive correlation with the length of PTV-Cinferior, with a correlation coefficient ranging from 0.523 to 0.797; the FJ IMRT plan exhibited better lung sparing in low-dose volumes than the JT VMAT plan. The FJ IMRT plan had similar MUs (888 ± 99) and delivery times (516.1 ± 54.7 s) as the JT IMRT plan (937 ± 194, 522 ± 5.6 s) but higher than SJ IMRT (713 ± 137, 488.8 ± 45.2 s) and JT VMAT plan (517 ± 59, 263.7 ± 43.3 s). CONCLUSIONS: The FJ IMRT technique is superior in reducing the low-dose volumes of lung tissues for patients with T-shaped esophageal cancer.

SWOT Analysis and Preliminary Study on Prevention and Control Management of Temporary Integrated Isolation Ward During COVID-19 Outbreak.

Background: The world faced crises of prevention and control and shortage of medical resources during the COVID-19 (Corona Virus Disease 2019) outbreak. The establishment of temporary integrated isolation wards in hospitals, which is universal and representative in China, is one of the most-effective strategies in solving these problems according to China's experiences. Aim: To conduct a preliminary study on the establishment of a temporary integrated isolation ward during the outbreak of COVID-19 and to evaluate related impact. Methods: SWOT analysis was used to analyze the advantages, disadvantages, opportunities, and risks in the establishment of the temporary integrated isolation ward, and corresponding corrective measures were made according to the analysis results. Findings: The ward has formulated more than 10 related work procedures and prevention and control measures. A total of 93 patients with 18 critically ill patients were admitted for treatment and isolation. They were all evaluated based on established procedures and protocols. Twenty-four supplementary nucleic acid tests were ordered and conducted. One new patient with COVID-19 was confirmed and was successfully transferred to the designated COVID-19 infectious control hospital. There were no missed diagnosis or misdiagnosis, no cross-infection of patients, no cluster outbreak, and no infection of medical workers during the entire process. Conclusion: SWOT analysis is helpful in guiding the establishment of a temporary integrated isolation ward and the formulation of prevention and control measures in Hebei General Hospital during the COVID-19 outbreak. It provides the guidance and reference of significance for the establishment of similar types of wards in the future.

The combined use of 2D scout and 3D axial CT images to accurately determine the catheter tips for high-dose-rate brachytherapy plans.

PURPOSE: To develop a method combining CT scout images with axial images to improve the localization accuracy of catheter tips in high-dose-rate (HDR) brachytherapy treatments. MATERIALS AND METHODS: CT scout images were utilized along with conventionally reconstructed axial images to aid the localization of catheter tips used during HDR treatment planning. A method was developed to take advantage of the finer image resolution of the scout images to more precisely identify the tip coordinates. The accuracies of this method were compared with the conventional method based on the axial CT images alone, for various slice thicknesses, in a computed tomography dose index (CTDI) head phantom. A clinical case which involved multiple interstitial catheters was also selected for the evaluation of this method. Locations of the catheter tips were reconstructed with the conventional CT-based method and this newly developed method, respectively. Location coordinates obtained via both methods were quantitatively compared. RESULTS: Combination of the scout and axial CT images improved the accuracy of identification and reconstruction of catheter tips along the longitudinal direction (i.e., head-to-foot direction, more or less parallel to the catheter tracks), compared to relying on the axial CT images alone. The degree of improvement was dependent on CT slice thickness. For the clinical patient case, the coordinate differences of the reconstructed catheter tips were 2.6 mm ± 0.9 mm in the head-to-foot direction, 0.4 mm ± 0.2 mm in the left-to-right direction, and 0.6 mm ± 0.2 mm in the anterior-to-posterior direction, respectively. CONCLUSION: Combining CT scout and axial images demonstrates the ability to provide a more accurate identification and reconstruction of the interstitial catheter tips for HDR brachytherapy treatment, especially in the longitudinal direction. The method developed in this work has the potential to be implemented clinically together with automatic segmentation in modern brachytherapy treatment planning systems, in order to improve the reconstruction accuracy of HDR catheters.

The clinical impact of removing rectal gas on high-dose-rate brachytherapy dose distributions for gynecologic cancers.

PURPOSE: To evaluate the impact of gas removal on bladder and rectal doses during intracavitary and interstitial high-dose-rate brachytherapy (HDRB) for gynecologic cancers. MATERIAL AND METHODS: Fifteen patients treated with definitive external beam radiation followed by HDRB for gynecologic cancers for a total of 21 fractions, presented with a significant amount of rectal gas at initial CT imaging (CTGAS ) after implantation. The gas was removed via rectal tubing followed by subsequent scan acquisition (CTCLINICAL ), which was used for planning and treatment delivery. To assess the effect of gas removal on dosimetry, both bladder and rectum volumes were recontoured on CTGAS . In order to evaluate the clinical impact on the total Equivalent-Dose-in-2Gy-fraction (EQD2 ), each fraction was also replanned to maintain clinically delivered target coverage (HRCTV D90). EQD2 D2cm3 for bladder and rectum were compared between plans. The Wilcoxon signed rank test was performed to evaluate statistically significant differences for all comparisons (P < 0.05). RESULTS: Mean rectum and bladder Dmax , D0.1cm3 , D1cm3 , D2cm3 , and D5cm3 were significantly different between CTGAS and CTCLINICAL . The mean percent increases on CTGAS for bladder were 12.3, 8.4, 9.9, 10.2, and 9.5% respectively and for rectum were 27.0, 19.6, 18.1, 18.5, and 19.4%, respectively. After replanning with CTGAS to maintain HRCTV D90 EQD2 , bladder and rectum EQD2 D2 cm3 resulted in significantly higher doses. The mean EQD2 D2 cm3 difference was 2.4 and 4.1 Gy for bladder and rectum, revealing a higher impact of gas removal on rectal DVH. CONCLUSION: Rectal gas removal resulted in statistically significant differences for both bladder and rectum. The resulting larger EQD2 D2 cm3 for bladder and rectum demonstrates that if patients were treated without removing gas, target coverage would need to be sacrificed to satisfy the rectum constraints and prevent toxicities. Therefore, this study demonstrates the importance of gas removal for gynecologic HDRB patients.

Proton beam therapy can achieve lower vertebral bone marrow dose than photon beam therapy during chemoradiation therapy of esophageal cancer.

Chemoradiation therapy plays an important role in both the neoadjuvant and definitive management of esophageal cancer (EC). Prior studies have suggested that advanced planning techniques can better spare organs at risk including the heart. Although multiple toxicities can result from esophageal radiotherapy, one less studied acute toxicity is that of myelosuppression, which can result, in part, from the combination of chemotherapy and incidental radiotherapy administration to the vertebral bodies (VBs), which abut the posterior aspect of the esophagus, especially in the lower thoracic esophagus. Traditionally, VB bone marrow doses are not accounted during EC radiation therapy planning. We sought to compare the doses to VBs between proton and photon radiation therapy as part of chemoradiation therapy for EC treatment. By reducing doses to the vertebrae, radiation therapy can decrease treatment-related myelosuppression, which can avoid delays or chemotherapy dose reductions in therapy, which likely affect long-term patient survival. Dose constraints are not routinely employed for bone marrow in radiation treatment planning. In our previous work, we identified thresholds to avoid grade ≥3 leukopenia, including VB V10Gy, VB V20Gy, and a mean VB dose (MVD) of 18.8 Gy. Herein we perform a retrospective dosimetric planning study comparing passive- or double-scattering proton beam therapy (PS-PBT), volumetric-modulated arc therapy (VMAT) (photon-based), and intensity-modulated radiation therapy (IMRT) (photon-based) in 25 patients with locally advanced EC who were treated originally with photon RT at our institution between 2011 and 2016. The aforementioned dose constraints were included in the retrospective planning process for PS-PBT, VMAT, and IMRT to determine the feasibility of achieving these VB constraints while maintaining reasonable target coverage and planned, consistent constraints to other organs at risk including lungs, spinal cord, and stomach. PS-PBT plans were found to achieve lower doses for VB V10Gy, V20Gy, and MVD than VMAT and static IMRT plans while achieving the same target coverage. PS-PBT resulted in lower organs at risk dosimetric parameters than the photon plans, with p < 0.0001. Student's paired t-test p-values in favor of proton therapy's ability to spare organs were as follows: for PS-PBT vs VMAT and PS-PBT vs IMRT in mean doses for lung, liver, and VB and VB V10Gy and VB V20Gy were all <0.001 (Bonferroni corrected α=0.017). One-way ANOVA found that VB doses (VB V10Gy, VB V20Gy, and MVD) were significantly lower for proton therapy (p < 0.006) among the 3 planning techniques.

Comprehensive Output Estimation of Double Scattering Proton System With Analytical and Machine Learning Models.

OBJECTIVES: The beam output of a double scattering proton system varies for each combination of beam option, range, and modulation and therefore is difficult to be accurately modeled by the treatment planning system (TPS). This study aims to design an empirical method using the analytical and machine learning (ML) models to estimate proton output in a double scattering proton system. MATERIALS AND METHODS: Three analytical models using polynomial, linear, and logarithm-polynomial equations were generated on a training dataset consisting of 1,544 clinical measurements to estimate proton output for each option. Meanwhile, three ML models using Gaussian process regression (GPR) with exponential kernel, squared exponential kernel, and rational quadratic kernel were also created for all options combined. The accuracy of each model was validated against 241 additional clinical measurements as the testing dataset. Two most robust models were selected, and the minimum number of samples needed for either model to achieve sufficient accuracy ( ± 3%) was determined by evaluating the mean average percentage error (MAPE) with increasing sample number. The differences between the estimated outputs using the two models were also compared for 1,000 proton beams with a randomly generated range, and modulation for each option. RESULTS: The polynomial model and the ML GPR model with exponential kernel yielded the most accurate estimations with less than 3% deviation from the measured outputs. At least 20 samples of each option were needed to build the polynomial model with less than 1% MAPE, whereas at least a total of 400 samples were needed for all beam options to build the ML GPR model with exponential kernel to achieve comparable accuracy. The two independent models agreed with less than 2% deviation using the testing dataset. CONCLUSION: The polynomial model and the ML GPR model with exponential kernel were built for proton output estimation with less than 3% deviations from the measurements. They can be used as an independent output prediction tool for a double scattering proton beam and a secondary output check tool for a cross check between themselves.

A novel approach to embed eye shields in customized bolus on nasal dorsum treatment for electron radiotherapy.

We aim to demonstrate the unique use of embedded lead eye shields in an electron wax bolus when treating the nasal dorsum. A patient presented to the clinic with squamous cell carcinoma of the nasal dorsum requiring treatment with en face electrons. A 3D customized wax bolus was designed and imported into the treatment planning system (TPS) to calculate the dose distribution. Due to high lens dose, the bolus was customized further to create 2 milled open slots in the wax, over the lens of eye, to allow lead sheets totaling 4 mm to be slid into the wax. The patient was brought back to the clinic to be scanned with the wax bolus fitting snugly over the nose, eyes, and cheek regions. The 3D milled insert holes were contoured on the CT in the TPS, assigned HU of 2758, to mimic the lead insertion. The lens dose with lead inserts was compared to the plan without lead insert. To further confirm the lens dose, EBT3 films were placed on the right and left eye under the bolus, and nose dorsum on the first day of treatment. The maximum dose of right lens, as calculated in the TPS with the simulated lead shields in place, decreased from 989.5cGy to 457cGy. The maximum dose of left lens decreased from 1085.4cGy to 501cGy. The dose readings from EBT3 films were in good agreement with the TPS, with deviation of 3.32%, 0.26%, and 3.44% for right lens, left lens, and nose, respectively. Daily positioning deviations compared to the plan were 0.65 ± 0.16cm and 0.63 ± 0.29cm for right eye and left eye, respectively. This novel device demonstrated the feasibility, in terms of dose calculation accuracy in the TPS and fabrication, of using customized bolus with lead inserts to conveniently shield the lens of the eyes in an electron treatment for the nose, enabling a streamlined daily setup.

The Impact of COVID-19 on Brachytherapy During the Pandemic: A Rutgers-Robert Wood Johnson Barnabas Health Multisite Experience.

PURPOSE: This study aimed to evaluate whether the coronavirus disease of 2019 (COVID-19) pandemic resulted in treatment delays in patients scheduled for or undergoing brachytherapy. METHODS AND MATERIALS: A retrospective cohort study was conducted across 4 affiliated sites after local institutional review board approval. The eligibility criteria were defined as all patients with cancer whose treatment plan included brachytherapy during the COVID-19 pandemic from February 24, 2020 to June 30, 2020. Treatment delays, cancellations, alterations of fractionation regimens, and treatment paradigm changes were evaluated. RESULTS: A total of 47 patients were eligible for the analysis. Median patient age at the time of treatment was 62 years (interquartile range, 56-70 years). Endometrial, cervical, and prostate cancers were the most common sites included in this analysis. Three patients (6.4%) with cervical cancer were diagnosed with COVID-19 during the course of their treatment. Interruptions of external beam radiation therapy (EBRT), cancellations of EBRT, cancellations of brachytherapy, and treatment delays due to COVID occurred in 5 (10.6%), 3 (6.4%), 8 (17%), and 9 (19%) patients, respectively. The mean and median number of days delayed for patients who experienced treatment interruptions were 16.3 days (standard deviation: 13.9 days) and 14 days (interquartile range, 5.75-23.75 days), respectively. For patients with cervical cancer, the mean and median overall treatment times defined as the time from the start of EBRT to the end of brachytherapy were 56 and 49 days, respectively. CONCLUSIONS: Despite the challenges the health care system faced during the pandemic, most patients with cancer were safely treated with minor treatment delays and interruptions. Long-term follow up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.

Development and Validation of a Radiomics Nomogram Model for Predicting Postoperative Recurrence in Patients With Esophageal Squamous Cell Cancer Who Achieved pCR After Neoadjuvant Chemoradiotherapy Followed by Surgery.

Background and purpose: Although patients with esophageal squamous cell carcinoma (ESCC) can achieve a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) followed by surgery, one-third of these patients with a pCR may still experience recurrence. The aim of this study is to develop and validate a predictive model to estimate recurrence-free survival (RFS) in those patients who achieved pCR. Materials and methods: Two hundred six patients with ESCC were enrolled and divided into a training cohort (n = 146) and a validation cohort (n = 60). Radiomic features were extracted from contrast-enhanced computed tomography (CT) images of each patient. Feature reduction was then implemented in two steps, including a multiple segmentation test and least absolute shrinkage and selection operator (LASSO) Cox proportional hazards regression method. A radiomics signature was subsequently constructed and evaluated. For better prediction performance, a clinical nomogram based on clinical risk factors and a nomogram incorporating the radiomics signature and clinical risk factors was built. Finally, the prediction models were further validated by calibration and the clinical usefulness was examined in the validation cohort to determine the optimal prediction model. Results: The radiomics signature was constructed using eight radiomic features and displayed a significant correlation with RFS. The nomogram incorporating the radiomics signature with clinical risk factors achieved optimal performance compared with the radiomics signature (P < 0.001) and clinical nomogram (P < 0.001) in both the training cohort [C-index (95% confidence interval [CI]), 0.746 (0.680-0.812) vs. 0.685 (0.620-0.750) vs. 0.614 (0.538-0.690), respectively] and validation cohort [C-index (95% CI), 0.724 (0.696-0.752) vs. 0.671 (0.624-0.718) vs. 0.629 (0.597-0.661), respectively]. The calibration curve and decision curve analysis revealed that the radiomics nomogram outperformed the other two models. Conclusions: A radiomics nomogram model incorporating radiomics features and clinical factors has been developed and has the improved ability to predict the postoperative recurrence risk in patients with ESCC who achieved pCR after nCRT followed by surgery.

A novel approach to Verify air gap and SSD for proton radiotherapy using surface imaging.

PURPOSE: To develop a novel approach to accurately verify patient set up in proton radiotherapy, especially for the verification of the nozzle - body surface air gap and source-to-skin distance (SSD), the consistency and accuracy of which is extremely important in proton treatment. METHODS: Patient body surfaces can be captured and monitored with the optical surface imaging system during radiation treatment for improved intrafraction accuracy. An in-house software package was developed to reconstruct the patient body surface in the treatment position from the optical surface imaging reference capture and to calculate the corresponding nozzle - body surface air gap and SSD. To validate this method, a mannequin was scanned on a CT simulator and proton plans were generated for a Mevion S250 Proton machine with 20 gantry/couch angle combinations, as well as two different snout sizes, in the Varian Eclipse Treatment Planning Systems (TPS). The surface generated in the TPS from the CT scan was imported into the optical imaging system as an RT Structure for the purpose of validating and establishing a benchmark for ground truth comparison. The optical imaging surface reference capture was acquired at the treatment setup position after orthogonal kV imaging to confirm the positioning. The air gaps and SSDs calculated with the developed method from the surface captured at the treatment setup position (VRT surface) and the CT based surface imported from the TPS were compared to those calculated in TPS. The same approach was also applied to 14 clinical treatment fields for 10 patients to further validate the methodology. RESULTS: The air gaps and SSDs calculated from our program agreed well with the corresponding values derived from the TPS. For the phantom results, using the CT surface, the absolute differences in the air gap were 0.45 mm ± 0.33 mm for the small snout, and 0.51 mm ± 0.49 mm for the large snout, and the absolute differences in SSD were 0.68 mm ± 0.42 mm regardless of snout size. Using the VRT surface, the absolute differences in air gap were 1.17 mm ± 1.17 mm and 2.1 mm ± 3.09 mm for the small and large snouts, respectively, and the absolute differences in SSD were 0.81 mm ± 0.45 mm. Similarly, for patient data, using the CT surface, the absolute differences in air gap were 0.42 mm ± 0.49 mm, and the absolute differences in SSD were 1.92 mm ± 1.4 mm. Using the VRT surface, the absolute differences in the air gap were 2.35 mm ± 2.3 mm, and the absolute differences in SSD were 2.7 mm ± 2.17 mm. CONCLUSION: These results showed the feasibility and robustness of using an optical surface imaging approach to conveniently determine the air gap and SSD in proton treatment, providing an accurate and efficient way to confirm the target depth at treatment.

Setup uncertainties and the optimal imaging schedule in the prone position whole breast radiotherapy.

BACKGROUND: To investigate the setup uncertainties and to establish an optimal imaging schedule for the prone-positioned whole breast radiotherapy. METHODS: Twenty prone-positioned breast patients treated with tangential fields from 2015 to 2017 were retrospectively enrolled in this study. The prescription dose for the whole breast treatment was 266 cGy × 16 for all of the patients and the treatments were delivered with the SSD setup technique. At every fraction of treatment, patient was firstly set up based on the body localization tattoos. MV portal imaging was then taken to confirm the setup; if discrepancy (> 3 mm) was found between the portal images and corresponding plan images, the patient positioning was adjusted accordingly with couch movement. Based on the information acquired from the daily tattoo and portal imaging setup, three sets of data, named as weekly imaging guidance (WIG), no daily imaging guidance (NIG), and initial 3 days then weekly imaging guidance (3 + WIG) were sampled, constructed, and analyzed in reference to the benchmark of the daily imaging guidance (DIG). We compared the setup uncertainties, target coverage (D95, Dmax), V5 of the ipsilateral lung, the mean dose of heart, the mean and max dose of the left-anterior-descending coronary artery (LAD) among the 4 imaging guidance (IG) schedules. RESULTS: Relative to the daily imaging guidance (IG) benchmark, the NIG schedule led to the largest residual setup uncertainties; the uncertainties were similar for the WIG and 3 + WIG schedules. Little variations were observed for D95 of the target among NIG, DIG and WIG. The target Dmax also exhibited little changes among all the IG schedules. While V5 of the ipsilateral lung changed very little among all 4 schedules, the percent change of the mean heart dose was more pronounced; but its absolute values were still within the tolerance. However, for the left-sided breast patients, the LAD dose could be significantly impacted by the imaging schedules and could potentially exceed its tolerance criteria in some patients if NIG, WIG and 3 + WIG schedules were used. CONCLUSIONS: For left-side whole breast treatment in the prone position using the SSD treatment technique, the daily imaging guidance can ensure dosimetric coverage of the target as well as preventing critical organs, especially LAD, from receiving unacceptable levels of dose. For right-sided whole breast treatment in the prone position, the weekly imaging setup guidance appears to be the optimal choice.

Insurance Approval for Proton Beam Therapy and its Impact on Delays in Treatment.

PURPOSE: Prior authorization (PA) has been widely implemented for proton beam therapy (PBT). We sought to determine the association between PA determination and patient characteristics, practice guidelines, and potential treatment delays. METHODS AND MATERIALS: A single-institution retrospective analysis was performed of all patients considered for PBT between 2015 and 2018 at a National Cancer Institute-designated Comprehensive Cancer Center. Differences in treatment start times and denial rates over time were compared, and multivariable logistic regression was used to identify predictors of initial denial. RESULTS: A total of 444 patients were considered for PBT, including 396 adult and 48 pediatric patients. The American Society for Radiation Oncology model policy supported PBT coverage for 77% of the cohort. Of adult patients requiring PA, 64% were initially denied and 32% remained denied after appeal. In patients considered for reirradiation or randomized phase 3 trial enrollment, initial denial rates were 57% and 64%, respectively. Insurance coverage was not related to diagnosis, reirradiation, trial enrollment, or the American Society for Radiation Oncology model policy guidelines, but it was related to insurance category on multivariable analysis (P < .001). Over a 3-year timespan, initial denial rates increased from 55% to 74% (P = .034). PA delayed treatment start by an average of 3 weeks (and up to 4 months) for those requiring appeal (P < .001) and resulted in 19% of denied patients abandoning radiation treatment altogether. Of pediatric patients, 9% were initially denied, all of whom were approved after appeal, and PA requirement did not delay treatment start (P = .47). CONCLUSIONS: PA requirements in adults represent a significant burden in initiating PBT and cause significant delays in patient care. Insurance approval is arbitrary and has become more restrictive over time, discordant with national clinical practice guidelines. Payors and providers should seek to streamline coverage policies in alignment with established guidelines to ensure appropriate and timely patient care.

Multiple primary malignancies in patients with anal squamous cell carcinoma.

Prior studies examining the risk of second primary malignancy (SPM) after a first primary cancer generally have used large datasets such as the Surveillance, Epidemiology, and End Results (SEER) registry and excluded survivors of previous primaries and developers of synchronous primaries. The goal of this study was to provide a more complete representation of multiple cancer risk in squamous cell carcinoma of the anus (SCCA) patients. A single-institution retrospective study of 46 patients treated definitively for SCCA between January 2006 and July 2017 was conducted. Of the 46 patients, 18 (39%) had either a primary malignancy before SCCA (n=9) or SPM after an index SCCA (n=9). Six patients had ≥3 total malignancies. In our cohort, patients without SPMs tended to die from SCCA recurrence, while patients with SPMs were more likely to die from their SPM than from SCCA. Our study suggests that patients with SCCA are often either survivors of previous cancers or develop later malignancies. Several risk factors may play a role including HPV infection, HPV-related or treatment-related immunosuppression, somatic mutations due to chemotherapy, and genetic factors. Patients with SCCA require lifelong surveillance given their elevated risk of malignancy. Future work should focus on identifying genomic or immunologic factors that may predispose SCCA patients to develop multiple primary malignancies.

Efficient double-scattering proton therapy with a patient-specific bolus.

PURPOSE: Passive scattering proton radiotherapy utilizes beam-specific compensators to shape the dose to the distal end of the tumor target. These compensators typically require therapists to enter the treatment room to mount between beams. This study investigates a novel approach that utilizes a single patient-specific bolus to accomplish the role of multi-field compensators to improve the efficiency of the treatment delivery. METHODS: Ray-tracing from the proton virtual source was used to convert the beam-specific compensators (mounted on the gantry nozzle) into an equivalent bolus thickness on the patient surface. The field bolus contours were combined to create a single bolus. A 3D acrylic bolus was milled for a head phantom. The dose distribution of the compensator plan was compared to the bolus plan using 3D Gamma analysis and film measurements. Boluses for two clinical patients were also designed. RESULTS: The calculated phantom dose distribution of the original proton compensator plan was shown to be equivalent to the plan with the surface bolus. Film irradiations with the proton bolus also confirmed the dosimetric equivalence of the two techniques. The dose distribution equivalency of the bolus plans for the clinical patients were demonstrated. CONCLUSIONS: We presented a novel approach that uses a single patient-specific bolus to replace patient compensators during passive scattering proton delivery. This approach has the potential to reduce the treatment time, the compensator manufacturing costs, the risk of potential collision between the compensator and the patient/couch, and the waste of compensator material.

Using gEUD based plan analysis method to evaluate proton vs. photon plans for lung cancer radiation therapy.

The goal of this study was to exam the efficacy of current DVH based clinical guidelines draw from photon experience for lung cancer radiation therapy on proton therapy. Comparison proton plans and IMRT plans were generated for 10 lung patients treated in our proton facility. A gEUD based plan evaluation method was developed for plan evaluation. This evaluation method used normal lung gEUD(a) curve in which the model parameter "a" was sampled from the literature reported value. For all patients, the proton plans delivered lower normal lung V5 Gy with similar V20 Gy and similar target coverage. Based on current clinical guidelines, proton plans were ranked superior to IMRT plans for all 10 patients. However, the proton and IMRT normal lung gEUD(a) curves crossed for 8 patients within the tested range of "a", which means there was a possibility that proton plan would be worse than IMRT plan for lung sparing. A concept of deficiency index (DI) was introduced to quantify the probability of proton plans doing worse than IMRT plans. By applying threshold on DI, four patients' proton plan was ranked inferior to the IMRT plan. Meanwhile if a threshold to the location of curve crossing was applied, 6 patients' proton plan was ranked inferior to the IMRT plan. The contradictory ranking results between the current clinical guidelines and the gEUD(a) curve analysis demonstrated there is potential pitfalls by applying photon experience directly to the proton world. A comprehensive plan evaluation based on radio-biological models should be carried out to decide if a lung patient would really be benefit from proton therapy.

Investigation on using high-energy proton beam for total body irradiation (TBI).

This work investigated the possibility of using proton beam for total body irradia-tion (TBI). We hypothesized the broad-slow-rising entrance dose from a monoen-ergetic proton beam can deliver a uniform dose to patient with varied thickness. Comparing to photon-based TBI, it would not require any patient-specific com-pensator or beam spoiler. The hypothesis was first tested by simulating 250 MeV, 275 MeV, and 300 MeV protons irradiating a wedge-shaped water phantom in a paired opposing arrangement using Monte Carlo (MC) method. To allow ± 7.5% dose variation, the maximum water equivalent thickness (WET) of a treatable patient separation was 29 cm for 250 MeV proton, and > 40 cm for 275 MeV and 300 MeV proton. The compared 6 MV photon can only treat patients with up to 15.5 cm water-equivalent separation. In the second step, we simulated the dose deposition from the same beams on a patient's whole-body CT scan. The maximum patient separation in WET was 23 cm. The calculated whole-body dose variations were ± 8.9%, ± 9.0%, ± 9.6%, and ± 14% for 250 MeV proton, 275 MeV proton, 300 MeV proton, and 6 MV photon. At last, we tested the current machine capability to deliver a monoenergetic proton beam with a large uniform field. Experiments were performed on a compact double scattering single-gantry proton system. With its C-shaped gantry design, the source-to-surface distance (SSD) reached 7 m. The measured dose deposition curve had 22 cm relatively flat entrance region. The full width half maximum field size was measured 105 cm. The current scatter filter had to be redesigned to produce a uniform intensity at such treatment distance. In con-clusion, this work demonstrated the possibility of using proton beam for TBI. The current commercially available proton machines would soon be ready for such task.