Equivalent Uniform Dose Research Articles

Exploratory Investigation of Dose-Linear Energy Transfer (LET) Volume Histogram (DLVH) for Adverse Events Study in Intensity-Modulated Proton Therapy (IMPT)

We proposed a novel tool of dose-linear-energy-transfer (LET) volume histogram (DLVH) and performed an exploratory study to investigate rectal bleeding in prostate cancer treated by intensity-modulated proton therapy (IMPT).DLVH was constructed with dose and LET as two axes, while the normalized volume of the structure was contoured in the dose-LET plane as iso-volume lines. We defined DLVH index, DLv% (d,l), i.e., v% of the structure have a dose of d ≥ Gy and an LET of l ≥ keV/µm similar to dose-volume histogram index Dv%. Nine prostate cancer patients with rectal bleeding (CTCAE grade ≥2) were included as the adverse event group, while 48 patients with no complication were considered as the control group. P-value map was constructed by comparison of the DLVH indices of all patients between the two groups using the Mann-Whitney U test. Dose-LET volume constraints (DLVCs) were derived based on the P-value map with a manual selection procedure facilitated by Spearman's correlation tests. The obtained DLVCs were further cross-validated using a multivariate support-vector-machine (SVM)-based normal tissue complication probability (NTCP) model with an independent testing dataset composed of 8 AE and 13 control patients.We extracted two DLVC constraints. One DLVC was obtained: V (dose/LET boundary: 2.5keV/μm at 75 Gy to 3.2keV/μm at 8.65 Gy) < 1.27% (DLVC1), revealing high LET volume effect. The second DLVC was observed: V(72.2 Gy,0keV/μm) < 2.23% (DVLC2), revealing high dose volume effect. The SVM-based NTCP model with two DLVCs provided slightly superior performance on training, validation, and testing compared to the model using generalized equivalent uniform dose (gEUD) alone (Table 1). The corresponding area-under-the-curves (AUCs) of the receiver operating characteristic (ROC) curve were 0.785 vs. 0.762, 0.720 vs. 0.704, and 0.798 vs. 0.779 for the training, validation, and testing dataset, respectively. Sensitivity of 0.67 and specificity of 0.69 were achieved at the NTCP cutoff value of 0.5 in validation.Our results demonstrated the importance of rectal "hot spots" in both high LET (DLVC1) and high dose (DLVC2) in inducing rectal bleeding. The SVM-based NTCP model confirmed the derived DLVCs as good predictors for rectal bleeding. The established NTCP model based on these two DLVCs has been used routinely at our proton center during the plan evaluation to minimize the possible incidence of rectal bleeding in prostate cancer patients treated by IMPT. Table 1 Performances of the NTCP models.

Reducing systematic errors due to deformation of organs at risk in radiotherapy.

In radiotherapy (RT), the planning CT (pCT) is commonly used to plan the full RT-course. Due to organ deformation and motion, the organ shapes seen at the pCT will not be identical to their shapes during RT. Any difference between the pCT organ shape and the organ's mean shape during RT will cause systematic errors. We propose to use statistical shrinkage estimation to reduce this error using only the pCT and the population mean shape computed from training data. The method was evaluated for the rectum in a cohort of 37 prostate cancer patients that had a pCT and 7-10 treatment CTs with rectum delineations. Deformable registration was performed both within-patient and between patients, resulting in point-to-point correspondence between all rectum shapes, which enabled us to compute a population mean rectum. Shrinkage estimates were found by combining the pCTs linearly with the population mean. The method was trained and evaluated using leave-one-out cross validation. The shrinkage estimates and the patient mean shapes were compared geometrically using the Dice similarity index (DSI), Hausdorff distance (HD), and bidirectional local distance. Clinical dose/volume histograms, equivalent uniform dose (EUD) and minimum dose to the hottest 5% volume (D5%) were compared for the shrinkage estimate and the pCT. The method resulted in moderate but statistically significant increase in similarity to the patient mean shape over the pCT. On average, the HD was reduced from 15.6 to 13.4mm, while the DSI was increased from 0.74 to 0.78. Significant reduction in the bias of volume estimates was found in the DVH-range of 52.5-65Gy, where the bias was reduced from -1.3 to -0.2 percentage points, but no significant improvement was found in EUD or D5%, CONCLUSIONS: The results suggest that shrinkage estimation can reduce systematic errors due to organ deformations in RT. The method has potential to increase the accuracy in RT of deformable organs and can improve motion modeling.

Yttrium-90 TOF-PET-Based EUD Predicts Response Post Liver Radioembolizations Using Recommended Manufacturer FDG Reconstruction Parameters.

PurposeExplaining why 90Y TOF-PET based equivalent uniform dose (EUD) using recommended manufacturer FDG reconstruction parameters has been shown to predict response.MethodsThe hot rods insert of a Jaszczak deluxe phantom was partially filled with a 2.65 GBq 90Y - 300ml DTPA water solution resulting in a 100 Gy mean absorbed dose in the 6 sectors. A two bed 20min/position acquisition was performed on a 550ps- and on a 320ps- TOF-PET/CT and reconstructed with recommended manufacturer FDG reconstruction parameters, without and with additional filtering. The whole procedure was repeated on both PET after adding 300ml of water (50Gy setup). The phantom was acquired again after decay by a factor of 10 (5Gy setup), but with 200min per bed position. For comparison, the phantom was also acquired with 18F activity corresponding to a clinical FDG whole body acquisition.ResultsThe 100Gy-setup provided a hot rod sectors image almost as good as the 18F phantom. However, despite acquisition time compensation, the 5Gy-setup provides much lower quality imaging. TOF-PET based sectors EUDs for the three large rod sectors agreed with the actual EUDs computed with a radiosensitivity of 0.021Gy-1 well in the range observed in external beam radiotherapy (EBRT), i.e. 0.01-0.04Gy-1. This agreement explains the reunification of the dose-response relationships of the glass and resin spheres in HCC using the TOF-PET based EUD. Additional filtering reduced the EUDs agreement quality.ConclusionsRecommended manufacturer FDG reconstruction parameters are suitable in TOF-PET post 90Y liver radioembolization for accurate tumour EUD computation. The present results rule out the use of low specific activity phantom studies to optimize reconstruction parameters.

Comparisons of normal tissue complication probability models derived from planned and delivered dose for head and neck cancer patients

Background and purposeNormal tissue complication probability (NTCP) models are typically derived from the planned dose distribution, which can deviate from the delivered dose due to anatomical day-to-day variations. The aim of this study was to compare NTCP models derived from the planned and the delivered dose for head and neck cancer (HNC) patients. Material and method322 HNC patients who received radiotherapy with daily CBCT guidance were included in this retrospective study. The delivered dose was estimated by deformably accumulating dose from daily CBCT to planning anatomy. We used a Lyman-Kutcher-Burman NTCP model, to relate the equivalent uniform dose (EUD) of organs at risk (OAR) with oral mucositis, xerostomia and dysphagia respectively. We compared the model parameters and performances. ResultsThe median differences between planned and delivered EUD to the OARs were significantly larger for patients with toxicity than without for acute dysphagia (≥G2 and ≥G3) and late dysphagia (≥G3) (p < 0.05). Those differences resulted in small differences in steepness and agreement to the data between delivered- and planned-fitted NTCP curves, and the differences were not significant. The differences in AUC were less than 0.01. ConclusionDifferences between delivered and planned dose did not lead to significant differences in NTCP curves. The additional clinical relevance of NTCP models using accumulated dose for oral mucositis, xerostomia and dysphagia in HNC radiotherapy is likely to be limited.

Dosimetric Comparison of Proton Versus Photon Radiosurgery for Treatment of Pituitary Adenoma

PurposeTo compare the dosimetric differences in stereotactic radiosurgery between use of passively scattered protons (PSRS) versus photons (XSRS) for pituitary adenomas. Methods and MaterialsNine patients with pituitary adenomas were selected among patients receiving single-fraction proton stereotactic radiosurgery (PSRS) between 2016 and 2017. These cases were replanned with XSRS using volumetric-modulated arc therapy with 2.5 mm and 5 mm multileaf collimators (2.5XSRS and 5XSRS, respectively). PSRS was planned with a dedicated single scattering stereotactic proton unit delivered via 3 equally or unequally weighted isocentric fields. XSRS plans were created with optimization to spare organs at risk. Plans were generated using the original total treatment dose delivered in 1 fraction. ResultsPlans were evaluated for target volume dosimetry and estimated clinical toxicity. There was no significant difference in clinical target volume V100%, V95%, V90% or homogeneity index between treatment modalities. PSRS offered lower maximum dose (Dmax) to organs at risk and equivalent uniform dose (EUD) compared with 5XSRS and 2.5XSRS, respectively, for critical structures including optic nerve (right, Dmax 4.18, 5.32, 5.41; EUD 3.35, 4.08, 4.20) and hypothalamus (Dmax 1.71, 3.94, 3.77; EUD 0.94, 2.47, 2.39; P < .05 for PSRS vs 5XSRS and 2.5XSRS). The projected risk of secondary tumors in excess of baseline was lowest for PSRS plans (PSRS 5.28, 5XSRS 12.93, 2.5XSRS 12.66 cases per 10,000 patient-years; P = .008 for PSRS vs 5XSRS, PSRS vs 2.5XSRS, and P = .77 for 5XSRS vs 2.5XSRS). ConclusionsWe demonstrate that neither modality has empirically superior dosimetry and identify potential clinical advantages as well as limitations of each technique. PSRS, 5XSRS and 2.5XSRS demonstrate comparable target volume dosimetry for pituitary adenoma. PSRS compared with XSRS modalities offers modestly decreased maximum dose and EUD to critical proximal structures and decreases risk of radiation-induced secondary tumors by more than half.

Individualised dosimetry and safety of SIRT for intrahepatic cholangiocarcinoma

BackgroundThe aim of this study was to investigate the safety and efficacy of selective internal radiation therapy (SIRT) with 90Y resin microspheres for the treatment of Intrahepatic Cholangiocarcinoma (ICC). A total of 23 SIRT procedures from 18 ICC subjects were analysed to determine a lesion-based dose/response relationship with absorbed dose measures from 90Y PET and metabolic response as measured on [18F]FDG PET. Average absorbed dose (Davg), minimum dose to 70% of the volume (D70), volume receiving at least 50 Gy (V50), biological effective dose (BED) and equivalent uniform dose (EUD), were compared to changes in metabolic volume, maximum standardised uptake value (SUVmax) and total lesion glycolysis (TLG). Dose to normal liver was assessed with changes in liver uptake rate as measured with [99mTc]mebrofenin scintigraphy for a cohort of 20 subjects with primary liver malignancy (12 ICC, 8 hepatocellular carcinoma (HCC)).ResultsThirty-four lesions were included in the analysis. A relationship was found between metabolic response and both Davg and EUD similar to that seen previously in metastatic colorectal cancer (mCRC), albeit trending towards a lower response plateau. Both dose and SUV coefficient of variation within the lesion (CoVdose and CoVSUV), baseline TLG and EUD were found to be mildly significant predictors of response. No strong correlation was seen between normal liver dose and change in [99mTc]mebrofenin liver uptake rate; low baseline uptake rate was not indicative of declining function following SIRT, and no subjects dropped into the ‘poor liver function’ category.ConclusionsICC lesions follow a similar dose–response trend as mCRC, however, despite high lesion doses a full metabolic response was rarely seen. The CoV of lesion dose may have a significant bearing on response, and EUD correlated more tightly with metabolic response compared to Davg. SIRT in primary liver malignancy appears safe in terms of not inducing a clinically significant decline in liver function, and poor baseline uptake rate is not predictive of a reduction in function post SIRT.

Dosimetric validation of two different radiobiological models for parotid gland functionality of tongue cancer

AbstractObjectiveThe aim of this study was to investigate the normal tissue complication probability (NTCP) for parotid gland of ca tongue patients from two different radiobiological models and to establish a dosimetric validity.MethodsLyman–Kutcher–Burman (LKB) model and linear quadratic (LQ) model were considered for determination of NTCP and tolerance dose (TD5/5 and TD50/5) for the parotid gland of 67 number of ca tongue patients who were treated with the volumetric arc therapy (VMAT) technique. An in‐house developed software on Excel (VBA) was used for this study.ResultsThe equivalent uniform dose (EUD) was linearly proportional to the effective volume (veff) for parotid glands and there was a strong correlation between EUD and veff. At EUD = 46 to 47 Gy, the NTCP of parotid was 0.5 for both the models. The tolerance doses, TD5/5 (veff) and TD50/5 (veff) were exponentially reduced with increase of veff for LKB model; whereas these parameters were volume‐independent in the LQ model. TD5/5 (veff) and TD50/5 (veff) were 31.98 Gy and 45.98 Gy respectively for all 67 patients in the LQ model. Below TD50/5, NTCP of LKB model was less than the NTCP , calculated from LQ model.ConclusionOne may consider radiobiological LQ model for estimation of clinical tolerance dose for OARs. Due to lack of clinical data, there are inaccuracy in determination of NTCP from LQ model. If sufficient number of tolerance data for partial volumes are available, the prediction of NTCP would be more confident.

Modelling Radiation-Induced Salivary Dysfunction during IMRT and Chemotherapy for Nasopharyngeal Cancer Patients.

Simple SummaryWe built a predictive model for acute salivary dysfunction for nasopharyngeal cancer patients receiving combined treatment. The final aim was to provide a nomogram (with dosimetric and clinical risk factors) to help physicians in the streamline prevention and management of this acute side effect. No research has focused on predicting acute xerostomia so far. We do not know if models predicting late xerostomia can also be applied to acute xerostomia, since different pathogenesis is suggested for acute and late events. The model was tested in two independent external cohorts. Validation results highlighted that the dosimetric part of the predictive model was highly generalisable, with the clinical risk part still being a weak component. The good validation of the model’s discriminative power and of the effect of the size of dosimetric factors created confidence for considering these factors while optimising radiotherapy.Background: Radiation-induced xerostomia is one of the most prevalent adverse effects of head and neck cancer treatment, and it could seriously affect patients’ qualities of life. It results primarily from damage to the salivary glands, but its onset and severity may also be influenced by other patient-, tumour-, and treatment-related factors. We aimed to build and validate a predictive model for acute salivary dysfunction (aSD) for locally advanced nasopharyngeal carcinoma (NPC) patients by combining clinical and dosimetric factors. Methods: A cohort of consecutive NPC patients treated curatively with IMRT and chemotherapy at 70 Gy (2–2.12 Gy/fraction) were utilised. Parotid glands (cPG, considered as a single organ) and the oral cavity (OC) were selected as organs-at-risk. The aSD was assessed at baseline and weekly during RT, grade ≥ 2 aSD chosen as the endpoint. Dose-volume histograms were reduced to the Equivalent Uniform Dose (EUD). Dosimetric and clinical/treatment features selected via LASSO were inserted into a multivariable logistic model. Model validation was performed on two cohorts of patients with prospective aSD, and scored using the same schedule/scale: a cohort (NPC_V) of NPC patients (as in model training), and a cohort of mixed non-NPC head and neck cancer patients (HNC_V). Results: The model training cohort included 132 patients. Grade ≥ 2 aSD was reported in 90 patients (68.2%). Analyses resulted in a 4-variables model, including doses of up to 98% of cPG (cPG_D98%, OR = 1.04), EUD to OC with n = 0.05 (OR = 1.11), age (OR = 1.08, 5-year interval) and smoking history (OR = 1.37, yes vs. no). Calibration was good. The NPC_V cohort included 38 patients, with aSD scored in 34 patients (89.5%); the HNC_V cohort included 93 patients, 77 with aSD (92.8%). As a general observation, the incidence of aSD was significantly different in the training and validation populations (p = 0.01), thus impairing calibration-in-the-large. At the same time, the effect size for the two dosimetric factors was confirmed. Discrimination was also satisfactory in both cohorts: AUC was 0.73, and 0.68 in NPC_V and HNC_V cohorts, respectively. Conclusion: cPG D98% and the high doses received by small OC volumes were found to have the most impact on grade ≥ 2 acute xerostomia, with age and smoking history acting as a dose-modifying factor. Findings on the development population were confirmed in two prospectively collected validation populations.

АНАЛИЗ ФИЗИЧЕСКОЙ И РАДИОБИОЛОГИЧЕСКОЙ ЭКВИВАЛЕНТНОСТИ РАССЧИТАННЫХ И ИЗМЕРЕННЫХ ДОЗОВЫХ РАСПРЕДЕЛЕНИЙ ДЛЯ СТЕРЕОТАКСИЧЕСКОЙ ТЕРАПИИ ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ

Purpose: Carrying out the analysis of the physical and radiobiological equivalence of dose distributions obtained during the planning of hypofractionated stereotactic radiation therapy of the prostate cancer and verification using a three-dimensional cylindrical dosimeter.&#x0D; Material and Methods: Based on the anatomical data of twelve patients diagnosed with prostate carcinoma, stage T2N0M0 with low risk, plans were developed for stereotactic radiation therapy with volumetric modulates arc therapy (VMAT). The dose per fraction was 7,25 Gy for 5 fractions (total dose 36,25 Gy) with a normal photon energy of 10 MV. The developed plans were verified using a three-dimensional cylindrical ArcCHECK phantom. During the verification process, the three-dimensional dose distribution in the phantom was measured, based on which the values of the three-dimensional gamma index and the dose–volume histogram within each contoured anatomical structures were calculated with 3DVH software.&#x0D; The gamma index value γ (3 %, 2 mm, GN) at a threshold equal to 20 % of the dose maximum of the plan and the percentage of coincidence of points at least 95 % was chosen as a criterion of physical convergence of the calculated and measured dose distribution according to the recommendations of AAPM TG-218. To analyze the radiobiological equivalence of the calculated and measured dose distribution, the local control probability (TCP) and normal tissue complication probability (NTCP) criteria were used based on the calculated and measured dose–volume histograms. Contours of the target (PTV) and the anterior wall of the rectum were used for the analysis. The approach based on the concept of equivalent uniform dose (EUD) by A. Niemierko was used to calculate the values of TCP/NTCP criteria.&#x0D; Results: The results of physical convergence of plans for all patients on the contour of the whole body were higher than 95 % for the criteria γ (3 %, 2 mm, GN). The convergence along the PTV contour is in the range (75.5–95.2)%. The TCP and NTCP values obtained from the measured dose-volume histograms were higher than the planned values for all patients. It was found that the accelerator delivered a slightly higher dose to the PTV and the anterior wall of the rectum than originally planned.&#x0D; Conclusion: The capabilities of modern dosimetric equipment allow us move to the verification of treatment plans based on the analysis of TCP / NTCP radiobiological equivalence, taking into account the individual characteristics of the patient and the capabilities of radiation therapy equipment.

Retrospective analysis of recurrence patterns and clinical outcome of grade II meningiomas following postoperative radiotherapy

BackgroundAtypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated.MethodsThe clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions.Results Data from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth.ConclusionsThe model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients’ stratification for dose escalation.

Analysis of Hepatocellular Carcinoma Stereotactic Body Radiation Therapy Dose Prescription Method Using Uncomplicated Tumor Control Probability Model

PurposeThis work was to establish an uncomplicated tumor control probability (UTCP) model using hepatocellular carcinoma (HCC) stereotactic body radiation therapy (SBRT) clinical data in our institution. The model was then used to analyze the current dose prescription method and to seek the opportunity for improvement. Methods and MaterialsA tumor control probability (TCP) model was generated based on local clinical data using the maximum likelihood method. A UTCP model was then formed by combining the established TCP model with the normal tissue complication probability model based on the study by Dawson et al. The authors investigated the dependence of maximum achievable UTCP on planning target volume equivalent uniform dose (EUD) at various ratio between planning target volume EUD and normal liver EUD (T/N EUD ratios). A new term uncomplicated tumor control efficiency (UTCE) was also introduced to analyze the outcome. A UTCE value of 1 implied that the theoretical maximum UTCP for the corresponding T/N EUD ratio was achieved. ResultsThe UTCE of the HCC SBRT patients based on the current dose prescription method was found to be 0.93 ± 0.05. It was found that the UTCE could be increased to 0.99 ± 0.03 by using a new dose prescription scheme, for which the UTCP could be maximized while keeping the normal tissue complication probability value smaller than 5%. ConclusionsThe dose prescription method of the current HCC SBRT in our institution was analyzed using a UTCP model established based on local clinical data. It was shown that there could be a potential to increase the prescription dose of HCC SBRT. A new dose prescription scheme was proposed to achieve better UTCP. Additional clinical trials would be required to validate the proposed dose prescription scheme in the future.

A Novel Fuzzy Logic Guided Method for Automatic gEUD-based Inverse Treatment Planning

Generalized equivalent uniform dose (gEUD) -based hybrid objective functions are widely used in intensity modulated radiotherapy (IMRT). To improve its efficiency, a novel fuzzy logic guided inverse planning method was developed for the automatic parameters optimization of the gEUD-based radiotherapy optimization. Simple inference rules were formulated according to the knowledge of the treatment planner. Then they automatically and iteratively guide the parameters modification according to the percentage of deviation between the current dose and the prescribed dose. weighting factors and prescribed dose were automatically adjusted by developed fuzzy inference system (FIS). The performance of the FIS was tested on ten prostate cancer cases. Experimental results indicate that proposed automatic method can yield comparable or better plans than manual method. The fuzzy logic guided automatic inverse planning method of parameters optimization can significantly improve the efficiency of the method of manually adjusting parameters, and contributes to the development of fully automated planning.

Prediction of Pituitary Gland Complications by LKB and Log-Logistic Radiobiological Models in 3D Conformal Radiation Therapy of Head and Neck Tumors

Introduction: The pituitary gland is frequently irradiated during radiation therapy of head and neck tumors which can influence the quality of life of the patients after radiation therapy. This study aimed to estimate the normal tissue complication probability (NTCP) for the pituitary gland in head and neck cancers using two radiobiological models. Material and Methods: 53 patients including 20 cases with nasopharyngeal cancer and 33 cases with brain tumor were studied. The dosimetric properties of each plan including minimum, mean and maximum doses were extracted from the dose-volume histogram curve. For estimation of pituitary gland response for each patient, the BIOPLAN software was used to calculate NTCP by LKB model and Matlab software was applied to calculate NTCP by equivalent uniform dose (EUD) model. Models’ parameters including TD50, , and‘a’ were extracted from a previous study of radiobiological modeling of pituitary gland response to radiation therapy. For statistical analysis, the T-test was used to compare two models. Results: The average mean doses of 30.42 and 51.29 (Gy) of the pituitary gland were obtained for nasopharyngeal and brain tumor patients, respectively. The average NTCPs of the pituitary gland for nasopharyngeal patients estimated by LKB and Log-logistic models were 3.84 and 3.91%, respectively. In brain tumors, the average NTCP was 16.33% for LKB and 16.41% for Log-logistic models. The results showed that the log-logistic and LKB models provided comparable results and no statistically significant difference (P-value< 0.05) was found between two models. Conclusion: The NTCP results indicated that the average NTCP of the pituitary gland for nasopharyngeal patients was approximately four times lower than that of brain tumors. Finally, implementation of follow up studies and modeling investigations are recommended for accurate estimation of pituitary gland complications following radiation therapy.

Assessment of the confidence interval in the multivariable normal tissue complication probability model for predicting radiation-induced liver disease in primary liver cancer.

We developed a confidence interval-(CI) assessing model in multivariable normal tissue complication probability (NTCP) modeling for predicting radiation-induced liver disease (RILD) in primary liver cancer patients using clinical and dosimetric data. Both the mean NTCP and difference in the mean NTCP (ΔNTCP) between two treatment plans of different radiotherapy modalities were further evaluated and their CIs were assessed. Clinical data were retrospectively reviewed in 322 patients with hepatocellular carcinoma (n = 215) and intrahepatic cholangiocarcinoma (n = 107) treated with photon therapy. Dose–volume histograms of normal liver were reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose. The most predictive variables were used to build the model based on multivariable logistic regression analysis with bootstrapping. Internal validation was performed using the cross-validation leave-one-out method. Both the mean NTCP and the mean ΔNTCP with 95% CIs were calculated from computationally generated multivariate random sets of NTCP model parameters using variance–covariance matrix information. RILD occurred in 108/322 patients (33.5%). The NTCP model with three clinical and one dosimetric parameter (tumor type, Child–Pugh class, hepatitis infection status and MLD) was most predictive, with an area under the receiver operative characteristics curve (AUC) of 0.79 (95% CI 0.74–0.84). In eight clinical subgroups based on the three clinical parameters, both the mean NTCP and the mean ΔNTCP with 95% CIs were able to be estimated computationally. The multivariable NTCP model with the assessment of 95% CIs has potential to improve the reliability of the NTCP model-based approach to select the appropriate radiotherapy modality for each patient.

Comparison of a Hybrid IMRT/VMAT technique with non-coplanar VMAT and non-coplanar IMRT for unresectable olfactory neuroblastoma using the RayStation treatment planning system—EUD, NTCP and planning study

The purpose of this study was to compare hybrid intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (Hybrid IMRT/VMAT), with non-coplanar (nc) IMRT and nc-VMAT treatment plans for unresectable olfactory neuroblastoma (ONB). Hybrid IMRT/VMAT, nc-IMRT and nc-VMAT plans were optimized for 12 patients with modified Kadish C stage ONB. Dose prescription was 65 Gy in 26 fractions. Dose–volume histogram parameters, conformation number (CN), homogeneity index (HI), integral dose and monitor units (MUs) delivered per fraction were assessed. Equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) based on the EUD model (NTCPLogit) and the Lyman–Kutcher–Burman model (NTCPLKB) were also evaluated. We found that the Hybrid IMRT/VMAT plan significantly improved the CN for clinical target volume (CTV) and planning treatment volume (PTV) compared with the nc-VMAT plan. In general, sparing of organs at risk (OARs) is similar with the three techniques, although the Hybrid IMRT/VMAT plan resulted in a significantly reduced Dmax to contralateral (C/L) optic nerve compared with the nc-IMRT plan. The Hybrid IMRT/VMAT plan significantly reduce EUD to the ipsilateral (I/L) and C/L optic nerve in comparison with the nc-IMRT plan and nc-VMAT plan, but the difference in NTCP between the three technique was <1%. We concluded that the Hybrid IMRT/VMAT technique can offer improvement in terms of target conformity and EUD for optic nerves, while achieving equal or better OAR sparing compared with nc-IMRT and nc-VMAT, and can be a viable radiation technique for treating unresectable ONB. However, the clinical benefit of these small differences in dosimetric data, EUD and NTCP of optic nerves may be minimal.

The Hippocampus: A New Organ at Risk for Postoperative Radiation Therapy for Bucco-alveolar Cancer? A Dosimetric and Biological Analysis

PurposeA significant proportion of patients with bucco-alveolar cancer are long-term survivors, warranting attention to survivorship issues. Decline in neurocognitive function after cranial irradiation for brain tumors correlates with a hippocampal maximum dose (Dmax) of more than 16 Gy, minimum dose (Dmin) of more than 9 Gy, and dose to 40% of the hippocampal volume (D40%) exceeding 7.3 Gy in 2-Gy equivalent dose (EQD2), respectively. We analyzed the utility of sparing the hippocampus in postoperative radiation therapy (PORT) for patients with bucco-alveolar cancer, given the proximity of target volumes to the hippocampus, by virtue of inclusion of the infratemporal fossa. Methods and MaterialsWe instituted hippocampal sparing for patients with bucco-alveolar cancer receiving PORT in March 2018. Ten prior and 10 subsequent consecutive patients with pathologically staged I-IVA cancers of the buccal mucosa, alveolus, and retromolar trigone formed the control group (no hippocampal sparing) and the study group (hippocampal sparing), respectively. The brain and temporal lobes were prescribed dose constraints in both groups. Patients received doses of 60 to 66 Gy at 2 Gy per fraction using the image-guided intensity modulated radiation therapy / volumetric modulated arc therapy technique. Treatment plans were evaluated for (1) hippocampal dosimetric parameters, (2) planning target volume dosimetry and plan-quality indices, and (3) biological indices of equivalent uniform dose (EUD) and normal-tissue complication probability (NTCP) for impaired neurocognitive function. ResultsHippocampal sparing significantly reduced the hippocampal DmaxEQD2, DmeanEQD2, and D40%EQD2 from 27 Gy to 10.9 Gy (P = .002), 14.3 Gy to 6.4 Gy (P = .002), and 15.5 Gy to 6.6 Gy (P = .005), respectively, with comparable plan-quality indices. The radiobiologically robust endpoints of ipsilateral hippocampal EUD (P = .005) and NTCP (P = .01) were statistically significantly improved. ConclusionsMeaningful dosimetric benefit, corroborated with radiobiological indices, was observed with hippocampal sparing. The feasibility and benefit of hippocampal sparing supports our view that the hippocampus should be incorporated as an organ at risk and attention should be given to neurocognitive function in patients with bucco-alveolar cancer who are receiving PORT.

Normal tissue complication probabilities (NTCP) of urethral stricture following salvage SBRT or HDR for periurethral recurrences following prior definitive radiation therapy.

246 Background: SBRT and HDR brachytherapy have emerged as definitive salvage re-irradiation options for men with locally recurrent prostate cancer after prior radiation therapy (RT). Toxicity with re-irradiation remains a concern in this setting, particularly for salvage of periurethral recurrences. We calculated the normal tissue complication probability (NTCP) of urethral stricture following salvage re-irradiation (HDR and SBRT) after previous definitive RT (external beam or HDR) for periurethral recurrences. Methods: Two upfront definitive treatment plans were generated for 5 men with localized prostate cancer: External Beam RT (EBRT1) to a dose of 79.2 Gy in 1.8 Gy fractions and HDR monotherapy (HDR1), 13.5 Gy x 2 implants. Periurethral recurrences were virtually created on diagnostic MRI scans for each of the five men and defined as a recurrent dominant intraprostatic lesion (DIL). Three salvage RT plans were generated for each patient (constraints in Table): HDR salvage (10 Gy whole gland; 13.5 Gy to DIL; 2 implants), SBRTr with maximal rectal sparing (constraints designed for salvage following prior EBRT; 30 Gy in 5 fractions whole gland; 40 Gy in 5 fractions to DIL), and SBRTu with maximal urethral sparing (constraints designed for patients with prior HDR monotherapy; same Rx). DVH data was collected for each plan (previous RT and each salvage approach) and the equivalent uniform dose (EUD) was calculated. NTCP for the urethral stricture in the summed plans (prior definitive treatment + each salvage plan) was calculated by the Lyman-Kutcher-Burman model using the following parameters: (α/β = 5Gy; TD50= 116.7; m = 0.23; n = 0.3). Results: Prescription coverage of 90% of the DIL volume was achieved for each plan. The mean NTCP of urethral stricture for EBRT1 + HDR salvage was 55.2% (range, 52.2-59.1%) and for HDR1 + HDR salvage was 49.2% (42.9-57.5%). For EBRT1 + SBRTr and EBRT1 + SBRTu the NTCP for urethral stricture was 54.0% (50.4-61.0%) and 43.2% (39.4-48.4%), respectively. The NTCP of urethral stricture for HDR1 + SBRTr was 48.1% (41.0-57.2%) and for HDR1 + SBRTu was 37.6% (30.9-44.6%). Conclusions: In this modeling analysis of salvage RT for periurethral recurrences following previous RT (EBRT or HDR monotherapy), the NTCP for urethral stricture was numerically lowest for salvage SBRT using maximum urethral sparing dose constraints in comparison to salvage SBRT with maximum rectal sparing constraints or salvage HDR brachytherapy. This type of analysis lends insight into personalized treatment planning based on previous RT modality and previous dose to organs at risk. Expanded analysis is underway. [Table: see text]

Dosimetric and radiobiological comparison of treatment plan between CyberKnife and EDGE in stereotactic body radiotherapy for pancreatic cancer

To perform a comparison of the different stereotactic body radiotherapy (SBRT) plans between the Varian EDGE and CyberKnife (CK) systems for locally advanced unresectable pancreatic cancer. Fifteen patients with pancreatic cancer were selected in this study. The median planning target volume (PTV) was 28.688 cm3 (5.736–49.246 cm3). The SBRT plans for the EDGE and CK were generated in the Eclipse and Multiplan systems respectively with the same contouring and dose constrains for PTV and organs at risk (OARs). Dose distributions in PTV were evaluated in terms of coverage, conformity index (CI), new conformity index (nCI), homogeneity index (HI), and gradient index (GI). OARs, including spinal cord, bowel, stomach, duodenum and kidneys were statistically evaluated by different dose-volume metrics and equivalent uniform dose (EUD). The volume covered by the different isodose lines (ISDL) ranging from 10 to 100% for normal tissue were also analyzed. All SBRT plans for EDGE and CK met the dose constraints for PTV and OARs. For the PTV, the dosimetric metrics in EDGE plans were lower than that in CK, except that D99 and GI were slightly higher. The EDGE plans with lower CI, nCI and HI were superior to generate more conformal and homogeneous dose distribution for PTV. For the normal tissue, the CK plans were better at OARs sparing. The radiobiological indices EUD of spinal cord, duodenum, stomach, and kidneys were lower for CK plans, except that liver were higher. The volumes of normal tissue covered by medium ISDLs (with range of 20–70%) were lower for CK plans while that covered by high and low ISDLs were lower for EDGE plans. This study indicated that both EDGE and CK generated equivalent plan quality, and both systems can be considered as beneficial techniques for SBRT of pancreatic cancer. EDGE plans offered more conformal and homogeneous dose distribution for PTV, while the CK plans could minimize the exposure of OARs.

Photon beam energy dependent single-arc volumetric modulated arc optimization.

The purpose of this work was to present a new single-arc mixed photon (6&18MV) VMAT (SAMP) optimization framework that concurrently optimizes for two photon energies with corresponding partial arc lengths. Owing to simultaneous optimization of energy dependent intensity maps and corresponding arc locations, the proposed model poses nonlinearity. Unique relaxation constraints based on McCormick approximations were introduced for linearization. Energy dependent intensity maps were then decomposed to generate apertures. Feasibility of the proposed framework was tested on a sample of ten prostate cancer cases with lateral separation ranging from 34 cm (case no.1) to 52cm (case no.6). The SAMP plans were compared against single energy (6MV) VMAT (SE) plans through dose volume histograms (DVHs) and radiobiological parameters including normal tissue complication probability (NTCP) and equivalent uniform dose (EUD). The contribution of higher energy photon beam optimized by the algorithm demonstrated an increase for cases with a lateral separation >40cm. SAMP-VMAT notably improved bladder and rectum sparing in large size cases. Compared to single energy, SAMP-VMAT plans reduced bladder and rectum NTCP in cases with large lateral separation. With the exception of one case, SAMP-VMAT either improved or maintained femoral heads compared to SE-VMAT. SAMP-VMAT reduced the nontarget tissue integral dose in all ten cases. A single-arc VMAT optimization framework comprising mixed photon energy partial arcs was presented. Overall results underline the feasibility and potential of the proposed approach for improving OAR sparing in large size patients without compromising the target homogeneity and coverage.

DVH Prediction for VMAT in NPC with GRU-RNN: An Improved Method by Considering Biological Effects.

Purpose A recurrent neural network (RNN) and its variants such as gated recurrent unit-based RNN (GRU-RNN) were found to be very suitable for dose-volume histogram (DVH) prediction in our previously published work. Using the dosimetric information generated by nonmodulated beams of different orientations, the GRU-RNN model was capable of accurate DVH prediction for nasopharyngeal carcinoma (NPC) treatment planning. On the basis of our previous work, we proposed an improved approach and aimed to further improve the DVH prediction accuracy as well as study the feasibility of applying the proposed method to relatively small-size patient data. Methods Eighty NPC volumetric modulated arc therapy (VMAT) plans with local IRB's approval in recent two years were retrospectively and randomly selected in this study. All these original plans were created using the Eclipse treatment planning system (V13.5, Varian Medical Systems, USA) with ≥95% of PGTVnx receiving the prescribed doses of 70 Gy, ≥95% of PGTVnd receiving 66 Gy, and ≥95% of PTV receiving 60 Gy. Among them, fifty plans were used to train the DVH prediction model, and the remaining were used for testing. On the basis of our previously published work, we simplified the 3-layer GRU-RNN model to a single-layer model and further trained every organ at risk (OAR) separately with an OAR-specific equivalent uniform dose- (EUD-) based loss function. Results The results of linear least squares regression obtained by the new proposed method showed the excellent agreements between the predictions and the original plans with the correlation coefficient r = 0.976 and 0.968 for EUD results and maximum dose results, respectively, and the coefficient r of our previously published method was 0.957 and 0.946, respectively. The Wilcoxon signed-rank test results between the proposed and the previous work showed that the proposed method could significantly improve the EUD prediction accuracy for the brainstem, spinal cord, and temporal lobes with a p value < 0.01. Conclusions The accuracy of DVH prediction achieved in different OARs showed the great improvements compared to the previous works, and more importantly, the effectiveness and robustness showed by the simplified GRU-RNN trained from relatively small-size DVH samples, fully demonstrated the feasibility of applying the proposed method to small-size patient data. Excellent agreements in both EUD results and maximum dose results between the predictions and original plans indicated the application prospect in a physically and biologically related (or a mixture of both) model for treatment planning.