The Investigating Image Registration Accuracy and Contour Propagation for Adaptive Radiotherapy Purposes in Line with the Task Group No. 132 Recommendation.

Purpose: Image registration is a crucial component of the adaptive radiotherapy workflow. This study investigates the accuracy of the deformable image registration (DIR) and contour propagation features of SmartAdapt, an application in the Eclipse treatment planning system (TPS) version 16.1. Materials and Methods: The registration accuracy was validated using the Task Group No. 132 (TG-132) virtual phantom, which features contour evaluation and landmark analysis based on the quantitative criteria recommended in the American Association of Physicists in Medicine TG-132 report. The target registration error, Dice similarity coefficient (DSC), and center of mass displacement were used as quantitative validation metrics. The performance of the contour propagation feature was evaluated using clinical datasets (head and neck, pelvis, and chest) and an additional four-dimensional computed tomography (CT) dataset from TG-132. The primary planning and the second CT images were appropriately registered and deformed. The DSC was used to find the volume overlapping between the deformed contours and the radiation oncologist (RO)-drawn contour. The clinical value of the DIR-generated structure was reviewed and scored by an experienced RO to make a qualitative assessment. Results: The registration accuracy fell within the specified tolerances. SmartAdapt exhibited a reasonably propagated contour for the chest and head-and-neck regions, with DSC values of 0.80 for organs at risk. Misregistration is frequently observed in the pelvic region, which is specified as a low-contrast region. However, 78% of structures required no modification or minor modification, demonstrating good agreement between contour comparison and the qualitative analysis. Conclusions: SmartAdapt has adequate efficiency for image registration and contour propagation for adaptive purposes in various anatomical sites. However, there should be concern about its performance in regions with low contrast and small volumes.

Impact of Interfractional Error on Dosiomic Features.

Objectives: The purpose of this study was to investigate the stability of dosiomic features under random interfractional error. We investigated the differences in the values of features with different fractions and the error in the values of dosiomic features under interfractional error. Material and Methods: The isocenters of the treatment plans of 15 lung cancer patients were translated by a maximum of ±3 mm in each axis with a mean of (0, 0, 0) and a standard deviation of (1.2, 1.2, 1.2) mm in the x, y, and z directions for each fraction. A total of 81 dose distributions for each patient were then calculated considering four fraction number groups (2, 10, 20, and 30). A total of 93 dosiomic features were extracted from each dose distribution in four different regions of interest (ROIs): gross tumor volume (GTV), planning target volume (PTV), heart, and both lungs. The stability of dosiomic features was analyzed for each fraction number group by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). The agreements in the means of dosiomic features among the four fraction number groups were tested by ICC. The percent differences (PD) between the dosiomic features extracted from the original dose distribution and the dosiomic features extracted from the dose distribution with interfractional error were calculated. Results: Eleven out of 93 dosiomic features demonstrated a large CV (CV ≥ 20%). Overall CV values were highest in GTV ROIs and lowest in lung ROIs. The stability of dosiomic features decreased as the total number of fractions decreased. The ICC results showed that five out of 93 dosiomic features had an ICC lower than 0.75, which indicates intermediate or poor stability under interfractional error. The mean dosiomic feature values were shown to be consistent with different numbers of fractions (ICC ≥ 0.9). Some of the dosiomic features had PD greater than 50% and showed different PD values with different numbers of fractions. Conclusion: Some dosiomic features have low stability under interfractional error. The stability and values of the dosiomic features were affected by the total number of fractions. The effect of interfractional error on dosiomic features should be considered in further studies regarding dosiomics for reproducible results.

Radiomic and Dosiomic Features for the Prediction of Radiation Pneumonitis Across Esophageal Cancer and Lung Cancer.

PURPOSE: The aim was to investigate the advantages of dosiomic and radiomic features over traditional dose-volume histogram (DVH) features for predicting the development of radiation pneumonitis (RP), to validate the generalizability of dosiomic and radiomic features by using features selected from an esophageal cancer dataset and to use these features with a lung cancer dataset. MATERIALS AND METHODS: A dataset containing 101 patients with esophageal cancer and 93 patients with lung cancer was included in this study. DVH and dosiomic features were extracted from 3D dose distributions. Radiomic features were extracted from pretreatment CT images. Feature selection was performed using only the esophageal cancer dataset. Four predictive models for RP (DVH, dosiomic, radiomic and dosiomic + radiomic models) were compared on the esophageal cancer dataset. We further used a lung cancer dataset for the external validation of the selected dosiomic and radiomic features from the esophageal cancer dataset. The performance of the predictive models was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve (ROCAUC) and the AUC of the precision recall curve (PRAUC) metrics. RESULT: The ROCAUCs and PRAUCs of the DVH, dosiomic, radiomic and dosiomic + radiomic models on esophageal cancer dataset were 0.67 ± 0.11 and 0.75 ± 0.10, 0.71 ± 0.10 and 0.77 ± 0.09, 0.71 ± 0.11 and 0.79 ± 0.09, and 0.75 ± 0.10 and 0.81 ± 0.09, respectively. The predictive performance of the dosiomic- and radiomic-based models was significantly higher than that of the DVH-based model with respect to esophageal cancer. The ROCAUCs and PRAUCs of the DVH, dosiomic, radiomic and dosiomic + radiomic models on the lung cancer dataset were 0.64 ± 0.18 and 0.37 ± 0.20, 0.67 ± 0.17 and 0.37 ± 0.20, 0.67 ± 0.16 and 0.45 ± 0.23, and 0.68 ± 0.16 and 0.44 ± 0.22, respectively. On the lung cancer dataset, the predictive performance of the radiomic and dosiomic + radiomic models was significantly higher than that of the DVH-based model. However, the PRAUC of the dosiomic-based model showed no significant difference relative to the corresponding RP prediction performance on the lung cancer dataset. CONCLUSION: The results suggested that dosiomic and CT radiomic features could improve RP prediction in thoracic radiotherapy. Dosiomic and radiomic feature knowledge might be transferrable from esophageal cancer to lung cancer.

Biological dosiomic features for the prediction of radiation pneumonitis in esophageal cancer patients.

OBJECTIVE: The purpose of this study was to develop a model using dose volume histogram (DVH) and dosiomic features to predict the risk of radiation pneumonitis (RP) in the treatment of esophageal cancer with radiation therapy and to compare the performance of DVH and dosiomic features after adjustment for the effect of fractionation by correcting the dose to the equivalent dose in 2 Gy (EQD2). MATERIALS AND METHODS: DVH features and dosiomic features were extracted from the 3D dose distribution of 101 esophageal cancer patients. The features were extracted with and without correction to EQD2. A predictive model was trained to predict RP grade ≥ 1 by logistic regression with L1 norm regularization. The models were then evaluated by the areas under the receiver operating characteristic curves (AUCs). RESULT: The AUCs of both DVH-based models with and without correction of the dose to EQD2 were 0.66 and 0.66, respectively. Both dosiomic-based models with correction of the dose to EQD2 (AUC = 0.70) and without correction of the dose to EQD2 (AUC = 0.71) showed significant improvement in performance when compared to both DVH-based models. There were no significant differences in the performance of the model by correcting the dose to EQD2. CONCLUSION: Dosiomic features can improve the performance of the predictive model for RP compared with that obtained with the DVH-based model.

Secondary cancer risk from modern external-beam radiotherapy of prostate cancer patients: Impact of fractionation and dose distribution.

Modern radiotherapy (RT) uses altered fractionation, long beam-on time and image-guided procedure. This study aimed to compare secondary cancer risk (SCR) associated with primary field, scatter/leakage radiations and image-guided procedure in prostate treatment using intensity-modulated RT (IMRT), CyberKnife stereotactic body RT (CK-SBRT) in relative to 3-dimensional conformal RT (3D-CRT). Prostate plans were generated for 3D-CRT, IMRT (39 fractions of 2 Gy), and CK-SBRT (five fractions of 7.25 Gy). Excess absolute risk (EAR) was calculated for organs in the primary field using Schneider's mechanistic model and concept of organ equivalent dose (OED) to account for dose inhomogeneity. Doses from image-guided procedure and scatter/leakage radiations were determined by phantom measurements. The results showed that hypofractionation relative to conventional fractionation yielded lower SCR for organs in primary field (p ≤ 0.0001). SCR was further modulated by dose-volume distribution. For organs near the field edge, like the rectum and pelvic bone, CK-SBRT plan rendered better risk profiles than IMRT and 3D-CRT because of the absence of volume peak in high dose region (relative risk [RR]: 0.65, 0.22, respectively, p ≤ 0.0004). CK-SBRT and IMRT generated more scatter/leakage and imaging doses than 3D-CRT (p ≤ 0.0002). But primary field was the major contributor to SCR. EAR estimates (risk contributions, primary field: scatter/leakage radiations: imaging procedure) were 7.1 excess cases per 104 person-year (PY; 3.64:2.25:1) for CK-SBRT, 9.93 (7.32:2.33:1) for IMRT and 8.24 (15.99:2.35:1) for 3D-CRT (p ≤ 0.0002). We conclude that modern RT added more but small SCR from scatter/leakage and imaging doses. The primary field is a major contributor of risk which can be mitigated by the use of hypofractionation.

RBE variation in prostate carcinoma cells in active scanning proton beams: In-vitro measurements in comparison with phenomenological models.

PURPOSE: In-vitro radiobiological studies are essential for modelling the relative biological effectiveness (RBE) in proton therapy. The purpose of this study was to experimentally determine the RBE values in proton beams along the beam path for human prostate carcinoma cells (Du-145). RBE-dose and RBE-LETd (dose-averaged linear energy transfer) dependencies were investigated and three phenomenological RBE models, i.e. McNamara, Rørvik and Wilkens were benchmarked for this cell line. METHODS: Cells were placed at multiple positions along the beam path, employing an in-house developed solid phantom. The experimental setup reflected the clinical prostate treatment scenario in terms of field size, depth, and required proton energies (127.2-180.1 MeV) and the physical doses from 0.5 to 6 Gy were delivered. The reference irradiation was performed with 200 kV X-ray beams. Respective (α/ß) values were determined using the linear quadratic model and LETd was derived from the treatment planning system at the exact location of cells. RESULTS AND CONCLUSION: Independent of the cell survival level, all experimental RBE values were consistently higher in the target than the generic clinical RBE value of 1.1; with the lowest RBE value of 1.28 obtained at the beginning of the SOBP. A systematic RBE decrease with increasing dose was observed for the investigated dose range. The RBE values from all three applied models were considerably smaller than the experimental values. A clear increase of experimental RBE values with LETd parameter suggests that proton LET must be taken into consideration for this low (α/ß) tissue.

MALAT1 Decreases the Sensitivity of Head and Neck Squamous Cell Carcinoma Cells to Radiation and Cisplatin.

BACKGROUND/AIM: Two-thirds of head and neck squamous cell carcinoma (HNSCC) patients present with locally advanced (LA) stages and have a poor survival rate. The aim of this study was to investigate the roles of the long non-coding RNAs MALAT1 on radiation and cisplatin sensitivity of HNSCC cells. MATERIALS AND METHODS: Clonogenic, cell viability, and apoptosis assays were performed in cells following MALAT1 knockdown using CRISPR/Cas9 system. RESULTS: MALAT1 was overexpressed in HNSCC cell lines as compared to a non-tumorigenic cell line. The number of colonies formed after radiation was significantly reduced in MALAT1 knockdown cells. The IC50 value of cisplatin in MALAT1 knockdown cells was lower than that of the control cells. MALAT1 knockdown resulted in cell cycle arrest at G2/M phase, DNA damage and apoptotic cell death. CONCLUSION: MALAT1 knockdown enhanced the sensitivity of HNSCC cells to radiation and cisplatin partly through the induction of G2/M cell cycle arrest resulting in DNA damage and apoptosis.

Investigating the impact of alpha/beta and LETd on relative biological effectiveness in scanned proton beams: An in vitro study based on human cell lines.

PURPOSE: A relative biological effectiveness (RBE) of 1.1 is commonly used in clinical proton therapy, irrespective of tissue type and depth. This in vitro study was conducted to quantify the RBE of scanned protons as a function of the dose-averaged linear energy transfer (LETd ) and the sensitivity factor (α/ß)X . Additionally, three phenomenological models (McNamara, Rørvik, and Jones) and one mechanistic model (repair-misrepair-fixation, RMF) were applied to the experimentally derived data. METHODS: Four human cell lines (FaDu, HaCat, Du145, SKMel) with differential (α/ß)X ratios were irradiated in a custom-designed irradiation setup with doses between 0 and 6 Gy at proximal, central, and distal positions of a 80 mm spread-out Bragg peak (SOBP) centered at 80 mm (setup A: proton energies 66.5-135.6 MeV) and 155 mm (setup B: proton energies 127.2-185.9 MeV) depth, respectively. LETd values at the respective cell positions were derived from Monte Carlo simulations performed with the treatment planning system (TPS, RayStation). Dosimetric measurements were conducted to verify dose homogeneity and dose delivery accuracy. RBE values were derived for doses that resulted in 90 % (RBE90 ) and 10 % (RBE10 ) of cell survival, and survival after a 0.5 Gy dose (RBE0.5Gy ), 2 Gy dose (RBE2Gy ), and 6 Gy dose (RBE6Gy ). RESULTS: LETd values at sample positions were 1.9, 2.1, 2.5, 2.8, 4.1, and 4.5 keV/µm. For the cell lines with high (α/ß)X ratios (FaDu, HaCat), the LETd did not impact on the RBE. For low (α/ß)X cell lines (Du145, SKMel), LQ-derived survival curves indicated a clear correlation of LETd and RBE. RBE90 values up to 2.9 and RBE10 values between 1.4 and 1.8 were obtained. Model-derived RBE predictions slightly overestimated the RBE for the high (α/ß)X cell lines, although all models except the Jones model provided RBE values within the experimental uncertainty. For low (α/ß)X cell lines, no agreement was found between experiments and model predictions, that is, all models underestimated the measured RBE. CONCLUSIONS: The sensitivity parameter (α/ß)X was observed to be a major influencing factor for the RBE of protons and its sensitivity toward LETd changes. RBE prediction models are applicable for high (α/ß)X cell lines but do not estimate RBE values with sufficient accuracy in low (α/ß)X cell lines.

Phantom design and dosimetric characterization for multiple simultaneous cell irradiations with active pencil beam scanning.

A new phantom was designed for in vitro studies on cell lines in horizontal particle beams. The phantom enables simultaneous irradiation at multiple positions along the beam path. The main purpose of this study was the detailed dosimetric characterization of the phantom which consists of various heterogeneous structures. The dosimetric measurements described here were performed under non-reference conditions. The experiment involved a CT scan of the phantom, dose calculations performed with the treatment planning system (TPS) RayStation employing both the Pencil Beam (PB) and Monte Carlo (MC) algorithms, and proton beam delivery. Two treatment plans reflecting the typical target location for head and neck cancer and prostate cancer treatment were created. Absorbed dose to water and dose homogeneity were experimentally assessed within the phantom along the Bragg curve with ionization chambers (ICs) and EBT3 films. LETd distributions were obtained from the TPS. Measured depth dose distributions were in good agreement with the Monte Carlo-based TPS data. Absorbed dose calculated with the PB algorithm was 4% higher than the absorbed dose measured with ICs at the deepest measurement point along the spread-out Bragg peak. Results of experiments using melanoma (SKMel) cell line are also presented. The study suggested a pronounced correlation between the relative biological effectiveness (RBE) and LETd, where higher LETd leads to elevated cell death and cell inactivation. Obtained RBE values ranged from 1.4 to 1.8 at the survival level of 10% (RBE10). It is concluded that dosimetric characterization of a phantom before its use for RBE experiments is essential, since a high dosimetric accuracy contributes to reliable RBE data and allows for a clearer differentiation between physical and biological uncertainties.

Characteristic of EBT-XD and EBT3 radiochromic film dosimetry for photon and proton beams.

Recently, a new type of radiochromic film, the EBT-XD film, has been introduced for high dose radiotherapy. The EBT-XD film contains the same structure as the EBT3 film but has a slightly different composition and a thinner active layer. This study benchmarks the EBT-XD against EBT3 film for 6 MV and 10 MV photon beams, as well as for 97.4 MeV and 148.2 MeV proton beams and 15-100 kV x-rays. Dosimetric and film reading characteristics, such as post irradiation darkening, film orientation effect, lateral response artifact (LRA), film sensitivity, energy and beam quality dependency were investigated. Furthermore, quenching effects in the Bragg peak were investigated for a single proton beam energy for both film types, in addition measurements were performed in a spread-out Bragg peak. EBT-XD films showed the same characteristic on film darkening as EBT3. The effects between portrait and landscape orientation were reduced by 3.1% (in pixel value) for EBT-XD compared to EBT3 at a dose of 2000 cGy. The LRA is reduced for EBT-XD films for all investigated dose ranges. The sensitivity of EBT-XD films is superior to EBT3 for doses higher than 500 cGy. In addition, EBT-XD showed a similar dosimetric response for photon and proton irradiation with low energy and beam quality dependency. A quenching effect of 10% was found for both film types. The slight decrease in the thickness of the active layer and different composition configuration of EBT-XD resulted in a reduced film orientation effect and LRA, as well as a sensitivity increase in high-dose regions for both photon and proton beams. Overall, the EBT-XD film improved regarding film reading characteristics and showed advantages in the high-dose region for photon and proton beams.