Dose-volume Parameters Research Articles

Artificial Intelligence–Based Autosegmentation: Advantages in Delineation, Absorbed Dose-Distribution, and Logistics

PurposeTo compare the performance of artificial intelligence (AI) in auto-contouring compared to a human practitioner in terms of precision, differences in dose distribution and time consumption. Methods and MaterialsDatasets of previously irradiated patients in three different segments (head and neck- (HNC), breast- (BC) and prostate cancer (PC)) were retrospectively collected. An experienced radiation oncologist (MD) performed organs-at-risk (OARs) and standard clinical target volume (CTV) delineations as baseline structures for comparison. AI-based auto-contours were generated in two additional CT copies; therefore, three groups were assessed: MD alone, AI alone, AI plus MD corrections (AI+C). Differences in Dice similarity coefficient (DSC) and person-hour burden were assessed. Furthermore, changes in clinically relevant dose-volume parameters were evaluated and compared. ResultsSeventy-five previously treated cases were collected (25 per segment) for the analysis. When compared to MD contours, the mean DSC scores were higher than 0.7 for 74% and 80% of AI and AI+C, respectively. After corrections, 17.1% structures presented DSC score deviations higher than 0.1 and 10.4% dose-volume parameters significantly changed in AI-contoured structures. The time consumption assessment yielded mean person-hour reductions of 68%, 51% and 71% for BC, PC and HNC, respectively. ConclusionIn great extent, AI yielded clinically acceptable OARs and certain CTVs in the explored anatomical segments. Sparse correction and assessment requirements place AI+C as a standard workflow. Minimal clinically relevant differences in OAR-exposure were identified. A substantial amount of person-hours could be repurposed with this technology.

Interplay Effect of Splenic Motion for Total Lymphoid Irradiation in Pediatric Proton Therapy.

(1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) Methods: Static and 4D CT images from ten patients were used for interplay effect simulations. Patients' original plans were optimized based on the average CT extracted from the 4D CT and planned with two posterior beams using scenario-based optimization (±3 mm of setup and ±3% of range uncertainty) and gradient matching at the level of mid-spleen. Dynamically accumulated 4D doses (interplay effect dose) were calculated based on the time-dependent delivery sequence of radiation fluence across all phases of the 4D CT. Dose volume parameters for each simulated treatment delivery were evaluated for plan quality; (3) Results: Peak-to-peak splenic motion (≤12 mm) was measured from the 4D CT of ten patients. Interplay effect simulations revealed that the ITV coverage of the spleen remained within the protocol tolerance for splenic motion, ≤8 mm. The D100% coverage for ITV spleen decreased from 95.0% (nominal plan) to 89.3% with 10 mm and 87.2% with 12 mm of splenic motion; (4) Conclusions: 4D plan evaluation and robust optimization may overcome problems associated with respiratory motion in proton TLI treatments. Patient-specific respiratory motion evaluations are essential to confirming adequate dosimetric coverage when proton therapy is utilized.

Prediction of Acute Radiation-Induced Lung Toxicity After Stereotactic Body Radiation Therapy Using Dose-Volume Parameters From Functional Mapping on Gallium 68 Perfusion Positron Emission Tomography/Computed Tomography

The aim of this work was to compare anatomic and functional dose-volume parameters as predictors of acute radiation-induced lung toxicity (RILT) in patients with lung tumors treated with stereotactic body radiation therapy. Fifty-nine patients treated with stereotactic body radiation therapy were prospectively included. All patients underwent gallium 68 lung perfusion positron emission tomography (PET)/computed tomography (CT) imaging before treatment. Mean lung dose (MLD) and volumes receiving x Gy (VxGy, 5-30 Gy) were calculated in 5 lung volumes: the conventional anatomic volume (AV) delineated on CT images, 3 lung functional volumes (FVs) defined on lung perfusion PET imaging (FV50%, FV70%, and FV90%; ie, the minimal volume containing 50%, 70%, and 90% of the total activity within the AV), and a low FV (LFV; LFV = AV - FV90%). The primary endpoint of this analysis was grade ≥2 acute RILT at 3 months as assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Dose-volume parameters in patients with and without acute RILT were compared. Receiver operating characteristic curves assessing the ability of dose-volume parameters to discriminate between patients with and without acute RILT were generated, and area under the curve (AUC) values were calculated. Of the 59 patients, 10 (17%) had grade ≥2 acute RILT. The MLD and the VxGy in the AV and LFV were not statistically different between patients with and without acute RILT (P > .05). All functional parameters were significantly higher in acute RILT patients (P < .05). AUC values (95% CI) for MLD AV, LFV, FV50%, FV70%, and FV90% were 0.66 (0.46-0.85), 0.60 (0.39-0.80), 0.77 (0.63-0.91), 0.77 (0.64-0.91), and 0.75 (0.58-0.91), respectively. AUC values for V20Gy AV, LFV, FV50%, FV70%, and FV90% were 0.65 (0.44-0.87), 0.64 (0.46-0.83), 0.82 (0.69-0.95), 0.81 (0.67-0.96), and 0.75 (0.57-0.94), respectively. The predictive value of PET perfusion-based functional parameters outperforms the standard CT-based dose-volume parameters for the risk of grade ≥2 acute RILT. Functional parameters could be useful for guiding radiation therapy planning and reducing the risk of acute RILT.

Hypoglossal nerve delineation in nasopharyngeal carcinoma patients may reduce the radiation dose and damage to the nerve

This study aims to establish a delineation guideline for the contouring of the hypoglossal nerve by dividing the nerve into different segments, and to test the possibility of a radiation dose reduction to the hypoglossal nerve in NPC patients receiving radiotherapy. Twenty NPC patients were selected arbitrarily. The hypoglossal nerves were delineated using anatomic landmarks and divided into the cisternal, intracanalicular, carotid, and transverse segments. The tumor coverage by radiation and dose-volume parameters of the nerve with and without various dose constraints to the hypoglossal nerve were compared. The hypoglossal nerve, which is invisible on CT images, can be delineated accurately with the assistance of several anatomic landmarks. Without a dose constraint to the hypoglossal nerve, the carotid space, intracanalicular, and transverse segments had high radiation dose-volumes. The dose-volume to the nerve, however, can be reduced when the nerve was defined and a dose constraint was given. The delineation of the hypoglossal nerve with its different segments is feasible. The carotid space, intracanalicular, and transverse segments received the highest dose, where the nerve damage was most likely located. The dose to the nerve can be reduced to less than 70 Gy using the intensity-modulated radiotherapy technique.

Model development of dose and volume predictors for esophagitis induced during chemoradiotherapy for lung cancer as a step towards radiobiological treatment planning

BackgroundCurrently, radiation therapy treatment planning system intends biological optimization that relies heavily upon plan metrics from tumor control probability (TCP) and normal tissue complication probability (NTCP) modeling. Implementation and expansion of TCP and NTCP models with alternative data is an important step towards reliable radiobiological treatment planning. In this retrospective single institution study, the treatment charts of 139 lung cancer patients treated with chemo-radiotherapy were reviewed and correlated dosimetric predictors with the incidence of esophagitis and established NTCP model of esophagitis grade 1 and 2 for lung cancer patients.MethodsEsophagus is an organ at risk (OAR) in lung cancer radiotherapy (RT). Esophagitis is a common toxicity induced by RT. In this study, dose volume parameters Vx (Vx: percentage esophageal volume receiving ≥ x Gy) and mean esophagus dose (MED) as quantitative dose-volume metrics, the esophagitis grade 1 and 2 as endpoints, were reviewed and derived from the treatment planning system and the electronic medical record system. Statistical analysis of binary logistic regression and probit were performed to have correlated the probability of grade 1 and 2 esophagitis to MED and Vx. IBM SPSS software version 24 at 5% significant level (α = 0.05) was used in the statistical analysis.ResultsThe probabilities of incidence of grade 1 and 2 esophagitis proportionally increased with increasing the values of Vx and MED. V20, V30, V40, V50 and MED are statistically significant good dosimetric predictors of esophagitis grade 1. 50% incidence probability (TD50) of MED for grade 1 and 2 esophagitis were determined. Lyman Kutcher Burman model parameters, such as, n, m and TD50, were fitted and compared with other published findings. Furthermore, the sigmoid shaped dose responding curve between probability of esophagitis grade 1 and MED were generated respecting to races, gender, age and smoking status.ConclusionsV20, V30, V40 and V50 were added onto Quantitative Analysis of Normal Tissue Effects in the clinic, or QUANTEC group’s dose constrains of V35, V50, V70 and MED. Our findings may be useful as both validation of 3-Dimensional planning era models and also additional clinical guidelines in treatment planning and plan evaluation using radiobiology optimization.

Validating a Simple Urethra Surrogate Model to Facilitate Dosimetric Analysis to Predict Genitourinary Toxicity.

The urethra may be a critical structure in prostate radiotherapy planning as some studies have shown that higher urethral dose correlates with worse genitourinary (GU) toxicity. Identifying the urethra requires an MRI planning scan or foley catheter insertion at CT planning. Most surrogates have been developed and validated against the urethra identified by a foley catheter. However, the urethral position can shift with catheter placement. We, therefore, aim to validate a simple urethra surrogate model against MRI-defined urethra. The surrogate model can be used to correlate urethra dose-volume parameters (DVP) with late GU toxicity and to apply urethral constraints in those with a CT-only based workflow. Thirty-nine MRI-defined urethras from patients in the PACE-C trial were assessed to determine the average position of the urethra in the midline sagittal prostate plane along the ¼ gland, midgland, ¾ gland, apex and 3mm below apex. Using these average positions, a Python script was developed, which places a 10mm diameter circle in the 1/4 gland, midgland, ¾ gland, apex and 3mm below the apex. The observer manually contours a 10mm circle at the prostate base (prostate-bladder neck interface) to infer the urethra position and interpolates the contours. The urethra surrogate model was compared against 20 MRI-defined urethras (within the treatment PTV) in patients treated with 36.25Gy in 5 fractions as part of the PACE-B trial. To assess the surrogate's geometric performance, the Dice similarity coefficient (DSC), Hausdorff distance (HD), mean surface distance to agreement (MDTA) and the percentage of MRI-defined urethra outside the surrogate (UOS) were calculated. The surrogate model's dosimetric performance was assessed by comparing the mean D99, D98, average dose, D50, D2 and D1 using a paired t-test. The D(n) is the dose (Gy) to (n)% of the urethra. The median results were: DSC 0.36 (IQR 0.28-0.42), HD 0.88cm (IQR, 0.70-1.04), MDTA 0.24cm (IQR, 0.21-0.28), UOS 29% (IQR, 17-52%). When comparing DVP between the MRI-defined urethra and surrogate urethra, the mean D99, D98 and D95 as 38.8Gy vs 39.1Gy (p = 0.17), 39.3Gy vs 39.5Gy (p = 0.23), 40.1Gy vs 40.4Gy (p = 0.21), respectively. The mean D50, average dose, D2 and D1 was 41.8Gy vs 41.9Gy (p = 0.03), 41.7 vs 41.8Gy (p = 0.04), 42.9Gy vs 43.0Gy (p = 0.05) and 43.0Gy vs 43.1Gy (p = 0.03), respectively. While there were geometric differences between the surrogate urethra and MRI-defined urethra, there was no statistically significant difference between most urethral dose-volume parameters (D99, D98, D95, and D1). Similarly, the actual differences in urethra DVP were not clinically significant. This surrogate model could be validated in a larger cohort and then used to estimate the urethra position on CT planning scans for dosimetric analysis in those without an MRI planning scan or urinary catheter.

Dose-Volume Parameters to the Urinary Tract Sub-Volumes and Predictors of Genitourinary Acute Toxicity in a Phase 2 Clinical Trial Assessing MRI-Guided Prostate Boost for Localized Prostate Cancer - The Miami BlastM Trial.

The relationship between radiotherapy dose to the sub-volumes of the genitourinary (GU) tract and GU toxicity is poorly understood, particularly in prostate cancer patients treated with an intraprostatic dominant lesion (IDL) boost. While the use of IDL boost improves outcomes, it results in higher doses to GU structures and potentially increased toxicity. We investigated the association between dose-volume histogram (DVH) parameters for urinary tract sub-volumes and GU toxicity in the context of IDL boost in patients enrolled in the Miami BlastM Trial. DVH data were assessed for patients enrolled in the Miami BlastM, a randomized phase 2 trial (NCT20140627) evaluating upfront versus integrated IDL boost. IDL GTV boost consisted of either 12-14 Gy administered on day 1 or integrated boost of 2.4 Gy per fraction (91.2 Gy total, 98.5 Gy 2.0 Equiv), with the prostate receiving 76 Gy in 38 fractions. Bladder trigone (BTg) and urethra sub-volumes were contoured retrospectively on planning CT scans. GU toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE) version 4 and International Prostate Symptom Score (IPSS). DVHs of the bladder, BTg, bladder minus BTg, prostatic urethra, and bulbomembranous urethra were examined. The primary composite endpoint was CTCAE GU acute toxicity grade (G) ≥2 and/or IPSS increase of ≥10 from baseline. Secondary endpoints were GU acute toxicity G≥2, GU late toxicity G≥2, and IPSS increase of ≥10 from baseline. Univariable and multivariable logistic regression analyses were performed. A total of 129 patients treated between February 2015 and January 2022 were eligible for analysis. One hundred and one (78%) patients developed either GU acute toxicity G≥2 (68%) and/or an IPSS increase of ≥10 from baseline (30%). Less than 2% of patients developed GU toxicity G≥3. BTg V30 Gy was significantly associated with IPSS increase ≥10 (p = 0.046). The bulbomembranous urethral maximum dose was significantly associated with GU acute toxicity G≥2 and GU late toxicity G≥2 (p <0.05 for both). Average maximum and mean urethral doses were 88.9 and 81.5 Gy, respectively. The BTg maximum dose, V20 Gy, V30 Gy, and V40 Gy were not significantly associated with the primary composite endpoint (p = 0.56, 0.75, 0.89, 0.82, respectively). On multivariable analysis, a higher bulbomembranous urethral maximum dose was significantly associated with GU acute toxicity G≥2 and/or IPSS increase of ≥10 from baseline (p = 0.019). Our data suggest a dose-effect relationship between maximum doses to the bulbomembranous urethra and GU toxicity. A better understanding of RT-related changes to specific sub-volumes of the urethra and strategies to mitigate urethral dose could enhance the therapeutic ratio in prostate cancer patients treated with MRI-guided IDL boost.

Comparison of Hybrid Techniques with 3D-Conformal Radiotherapy in Patients with Lung Cancer

Purpose: It’s postulated that hybrid techniques (HT) with lower weighting of IMRT/VMAT component would improve lung dose-volume parameters despite some disadvantage in PTV homogeneity index (HI) and target coverage (TC). &#x0D; Material and Methods: Conformal plans were prepared using 6-10-15 MV-X photon energies while IMRT/VMAT plans of HTs were prepared using 6MV-X. Four HTs were developed having two different ratios (10% and 50%) of IMRT/VMAT component (h-IMRT1, h-IMRT2 and h-VMAT1, h-VMAT2, respectively). HTs were compared with 3D-CRT in terms of HI and TC for PTV, and total lung (TL) and contralateral lung (CL) V5Gy, V10Gy, V20Gy and mean lung dose (MLD). &#x0D; Results: All HTs were advantageous for HI and TC, while disadvantageous for TL and CL-V5Gy. H-IMRT2 provided better TC than h-IMRT1, and so did h-VMAT2 compared to h-VMAT1. Lower weighting of IMRT/VMAT decreased TL and CL-V5Gy in HTs. In addition, h-IMRT1 decreased TL and CL-MLD and CL-V20Gy compared to h-IMRT2, while h-VMAT2 decreased TL-V20Gy and CL-MLD compared to h-VMAT2. &#x0D; Conclusion: In the RT of lung tumors close to vertebra, it may be appropriate to suggest a ratio of IMRT/VMAT component about 10% in order to decrease the low and intermediate dose-wash lung volume, if HI and TC values are acceptable.

Correlation of Dose Volume Parameters with Dysphagia and Pharyngeal Constrictor Muscle Thickness in Dysphagia Optimized IMRT

Reduced radiation dose to the pharyngeal constrictor muscles (PCM) using dysphagia optimized intensity-modulated RT (DO-IMRT) is associated with improved swallowing outcomes in oropharyngeal cancers (OPCs). Purpose was to evaluate the relationship between dose of radiation delivered and acute dysphagia in patients with OPC treated with IMRT, after delineation of PCM. Twenty-five patients with newly diagnosed OPC who underwent definitive IMRT with concurrent cisplatin were included in the study. PCM mean dose < 50 Gy was used as the dose constraint. Target volume was divided into high, intermediate and low risk areas receiving doses in the range of 60-66 Gy, 54-58 Gy, 51-56 Gy in 30-33 fractions over 6-6.5 weeks, respectively. PCM dose-volume parameters were collected and logistic regression was used to analyze these data relative to percent weight loss during RT and duration of feeding tube use. Thickness of constrictor muscle in pre-treatment and 3 months post-therapy CT scan were assessed. Weekly assessment of dysphagia was based on RTOG toxicity gradings. Aim of the study was to evaluate the correlation between dysphagia grades with dose-volume parameters and PCM thickness. Median age was 55.0 years (mean 54.3) with 24 males and stage II:III-16:9 patients. Dmean to PCM was 49.86 Gy (range 48.22 -57.63) with median Dmax of 70.24 Gy. For patients with dysphagia (grade ≥1), V50 ranged from 48.2-57.23%, while in those with no dysphagia, it ranged from 47.92-52.18 % (Mean 51.36%). Nine patients needed feeding tube after RT end. Median feeding tube duration was 64 days. The correlation between Dmean ≥ 50 Gy and dysphagia at 1st, 2nd, 3rd and 6th month was found statistically significant (p < 0.01). Table 1 shows the Pearson correlation and P-value of the dosimetric parameters with dysphagia. The correlation of V50 was found statistically significant with grade of dysphagia at 3rd and 6th month post-treatment (p<0.001). The mean thickness range and median thickness of constrictors before and 3 months after treatment were 1.8-3.2 mm, 2.4 mm, and 2.8-6.2 mm,4.1 mm, respectively. The increase in thickness of constrictor muscle correlated significantly (p<0.05) with dysphagia grades and also with V50, V60 and Dmean (p<0.001) but no statistical significance was seen with Dmax (p = 0.232). With a median follow-up of 18 months (range 7-24), 1-year actuarial local control was 92%. DO-IMRT may prove beneficial in the OPC by preventing dysphagia and aspiration post therapy and hence improving the quality of life of patients. Dmean ≥ 50Gy, V50 > 51.4% and V60 > 35.5% are the parameters correlating significantly with dysphagia (p<0.001) and change in mean thickness of PCM (p<0.001).

Development and Validation of CT-Based Dose-Volume-Radiomics Nomogram for Radiation Induced Hypothyroidism in Nasopharyngeal Carcinoma

Several studies reported hypothyroidism occurred in 40-50% of patients who were treated with neck irradiation. Post-radiation hypothyroidism impairs quality of life, increases the risk of cardiac complications, and requires lifelong thyroxine replacement in affected patients. At present, radiation dose-volume constraints of thyroid gland are used to predict thyroid function outcomes in patients with nasopharyngeal carcinoma (NPC). However, it is limited by (a) inferior predictive power, (b) a lack of analyzing individualized thyroid characteristics as a categoriad to predict radiation induced hypothyroidism (RIHT). In this study, we firstly developed and validated CT-based dose-volume-radiomics nomogram to predict RIHT in patients with NPC. A total of 451 NPC patients who underwent definitive radiotherapy were randomly assigned into the training (n = 338) and validation set (n = 113) in a 3:1 ratio. Dose-volume parameters, including the thyroid volume, mean dose (Dmean), percentage of the volume that received xGy of radiation (Vx), and the absolute volume that was spared from xGy of radiation (Vsx), were collected from radiotherapy planning databases. We defined primary hypothyroidism as an elevated TSH serum level (> 4.94 mIU/L) in combination with a normal or low serum FT4 level, regardless of symptoms. 1316 CT radiomic features were extracted and selected to construct the radiomics signature (RS). A CT-based nomogram was established by integrating clinical factors, dose-volume parameters and radiomics signature in training set and was tested in validation set. With a median follow-up period of 68 months, 301 (66.7%) patients developed RIHT. Compared with other dose-volume parameters including thyroid volume, V30, V50, Dmean, Vs45, Vs50, the thyroid volume spared from 60Gy (Vs60) had best power to predict RIHT. The radiomics signature constructed by 8 selected radiomic features showed better prognostic performance than Vs60 for predicting RIHT in training set (RIHT vs. Vs60, C-index: 0.69 vs. 0.58) and internal validation set (C-index: 0.65 vs. 0.55). Patients were stratified into high- and low-risk groups by median radiomic signature. Patients in high-risk group had higher rate of RIHT than patients in low-risk group (training set:61% vs.39%, P<0.05; validation set: 73% vs.32%, P<0.05). The nomogram established by integrating radiomics signature with Vs60 showed optimal prognostic performance with C-index of 0.71 in training, 0.66 in validation set. Calibration curves showed good agreement. CT-based dose-volume-radiomics nomogram provided an excellent prognostic tool for predict incidence rate of RITH in patients with NPC received definitive radiotherapy.

An Attempt to Reduce Lung Dose-Volume in the Era of Radiotherapy Combined Immunotherapy

In immunotherapy era, the safety of thoracic radiotherapy, especially pneumonia is a concern of clinical and patients. The incidence of pneumonia in KEYNOTE 799 is higher than that in PACIFIC and GEMSTONE301, and the incidence of pneumonia is related to V20 Gy. This study aims to explore how to reduce the lung dose of immunotherapy plus concurrent chemoradiation therapy (cCRT). We prospectively selected 32 patients treat with IMRT for untreated, locally advanced, stage III NSCLC. They all received immunochemotherapy in the first cycle treatment and completed the first CT-based simulation. In the second cycle treatment, all patients received cCRT plus ICIs and each patient received the second radiotherapy location after 10 or 20 fractions of radiotherapy. The initial and second treatment plan based on CT image are Plan1 and Plan2. The volume changes of gross tumor volume (GTV) between primary and secondary CT scans were compared, and the dose-volume parameters such as lung volume (V5 Gy, V20 Gy, V30 Gy) and heart volume (V30 Gy) in Plan2 were compared with those of Plan1. Compared with the first and second CT scan, the mean volume of GTV is decreased by 34%. The dose-volume parameters of total lung and heart were significantly lower than those in Plan1.Among them the V20 Gy, V30 Gy of total lung have statistical difference (Z = -2.068, P = 0.039; Z = -3.008, P = 0.003; respectively) and decreased by 31%, 33%, respectively. Additionally, the V20 resected after the 10-fraction radiotherapy is less than the 20th (V20 Gy = 25.1%, 26.3%; respectively). Meanwhile, for treatment-related pneumonitis, there is only one case (5%) in grade 3 or higher pneumonitis, and most of pneumonitis can be relieved after symptomatic treatment. In the mode of immunotherapy plus cCRT, timely reduction measures in the process of radiotherapy will effectively reduce lung dose-volume (V20 Gy), so as to decrease pulmonary toxicity. Two-cycle induction therapy were followed by radiotherapy may be a potent treatment candidate.

Comparison of Early Outcomes of Stereotactic Accelerated Partial Breast Irradiation vs. Volumetric Modulated Arc Therapy-Based FAST-FORWARD Whole Breast Irradiation for Breast Cancer

Despite evidence supporting APBI from 8 published prospective randomized trials enrolling over 10,000 women, the uptake of APBI in clinical practice is surprisingly low. This is being exacerbated by a new, convenient, and safe shortened WBI schedule. Here, we report the dosimetric and early outcome analyses of the first >1000 patients treated at our institution since the first adoption of stereotactic APBI and the ultra-hypofractionated WBI regimen. From 2016 to 2022, 801 women with breast cancers in the suitable or cautionary categories according to the ASTRO APBI consensus panel guidelines, received 30 Gy in 5 fractions (92%) either using a robotic stereotactic radiation system (83%) or stereotactic volumetric-based arc therapy (VMAT, 17%). Between 2020 and 2022, 468 women, who were not candidates for APBI and not undergoing any regional irradiation received 26 Gy in 5 fractions using VMAT to the whole breast with the addition of cardiac sparing technique in left-sided breast cancer patients. Tumor bed boosts were delivered in 99% of FF-WBI patients. We evaluated dose-volume histogram parameters for target volumes and organs-at-risk and radiation-related toxicities during RT or within 6 months after the end of RT. Target volume coverage was acceptable in both groups, with mean 96% of the target volumes receiving 95% of the prescribed doses and 0 cm3 within target volumes exceeding 105% of the prescribed doses. S-APBI resulted in small, but statistically significant, reductions in the radiation dose delivered to the ipsilateral breast, contralateral breast, lungs, heart, and coronary artery compared with FF-WBI. Comparing WBI to APBI, the mean contralateral breast dose, ipsilateral lung V20 Gy, mean contralateral lung dose, and mean heart dose, were reduced by 89%, 78%, 73%, and 29%, respectively. With median follow-up periods of 32 months for s-APBI and 19 months for FF-WBI, acute toxicity was assessable in all patients. The risks of any grade acute toxicity were 21% for s-APBI and 25% for FF-WBI (p = .117). Among them, grade 2 rates were 1.3% in both groups and no severe toxicity has been reported. We found s-APBI and VMAT-based FF WBI were associated with favorable dosimetric and acute toxicity profiles. However, considering significantly less irradiated volume in the breast, lungs, and heart, APBI with advanced available technique options should be considered over any WBI-based approach for patients at low risk for local recurrence.

A Comparison of Two Plan Optimization Methods in Three-Dimensional Brachytherapy for Cervical Cancer

To compare dose distributions created by using two Inverse Planning Simulated Annealing (IPSA) and Hybrid Inverse Planning Optimization (HIPO) in three-dimensional (with CT image guidance) brachytherapy planning for cervical cancer. Brachytherapy plans for thirty patients with cervical cancer were created using the IPSA and HIPO algorithms (The IPSA algorithm is calculated based on the anatomical structure, and the simulated annealing algorithm is used to optimize the residence time, and the HIPO algorithm is the optimization and replacement for the IPSA). To obtain a HIPO plan, a manually optimized post-loading treatment plan was applied to these 30 patients, and then the treatment plan was reoptimized using the HIPO algorithm based on the original image information. Individual patients will consider interpolation therapy according to the needs of their condition. The types of plans were compared based on a variety of dose volume parameters, including the mean dose covering 90% of high-risk clinical target volume (D90 for HR-CTV), the mean dose to 2 cm3 volume (D2cc) for bladder, rectum, intestine and sigmoid, and average treatment time were compared and analyzed. Compared with the two groups of plans, mean value of HR-CTV D90 for the HIPO plans was (585 cGy), which was significantly higher than that for the IPSA plans (567 cGy. This difference is statistically significant (P<0.05). The HIPO plans had mean D2cc 422±47 cGy for bladder, 403±38 cGy for rectum, which were lower than those from the SA plans, i.e., 446±42 cGy for bladder and 427±31 cGy for rectum; These differences were statistically significant (t = 5.125, 4.729, P <0.05). There was no statistically significant difference in the sigmoid D2cc doses between the two algorithms. The treatment times for delivering the two types of plans were not significant different. Depending on patient's condition, whether conventional brachytherapy therapy or interpolation therapy is used, the use of the HIPO algorithm to design the treatment regimen without additional treatment time can provide a higher target dose than the manually optimized brachytherapy regimen. Meanwhile, the bladder and rectum doses can be reduced to a certain extent under the premise of ensuring that the target dose met the treatment requirements. There is some increasement for the intestine dose with HIPO planning group, but the dose limits required by the guidelines are still met clinical requirement.

Dosimetric Comparison of Nodal Clinical Target Volume for Locally Advanced Non-Small Cell Lung Cancer: Options for Geometric Expansion vs. Lymph Node Stations

We investigated whether dosimetric differences existed in nodal clinical target volume (CTV) using options for geometric expansion and lymph node stations based on the European Society for Radiotherapy and Oncology (ESTRO) guideline for locally advanced non-small cell lung cancer (NSCLC). With treatment planning computed tomographic images in 17 patients who underwent radiotherapy for cT4N2M0 NSCLC from 2017 to 2022 at our institution, we retrospectively contoured nodal CTVs based on the guideline's options of: (1) geometric expansion, CTV including the nodal gross tumor volume plus 5 mm margin: (2) lymph node stations, CTV including the affected lymph node stations. The 5 mm margins for planning target volume (PTV) were added to the nodal and primary tumors' CTVs. Treatment planning of 60 Gy in 30 fractions to the PTV D50% was performed using volumetric modulated arc therapy; Dn% was irradiated dose to n% of volume of the structure; VnGy was percentage of volume of the structure at least irradiated n Gy. We compared dose-volume parameters between the two options using Wilcoxon rank sum test. Primary tumors were located in the right and left lobes in 12 and five patients, and in the upper and lower lobes in 13 and four patients, respectively. Median PTV size/D95% of the options for geometric expansion and lymph node stations were 569 cc (range, 149-2005 cc)/58.2 Gy (range, 57.5-58.7 Gy) and 635 cc (range, 184-2109 cc)/58.1 Gy (range, 57.5-58.7 Gy), respectively. Median mean dose of the esophagus/heart in the two options were 12.2 Gy (range, 6.6-24.9 Gy)/3.3 Gy (range, 0.6-19.1 Gy) and 16.1 Gy (range, 13.6-30.5 Gy)/4.6 Gy (range, 0.7-18.9 Gy), respectively. Median V20 Gy/mean dose of the lungs in the options for geometric expansion and lymph node stations were 20.5% (range, 14.8-33.9%)/12.2 Gy (range, 8.7-18.4 Gy) and 24.0% (range, 15.1-36.7%)/13.5 Gy (range, 9.5-19.4 Gy), respectively. In the eight patients (47%) with lymph node metastases in stations 2 or 3, a significant dosimetric difference between the two options existed on V20 Gy of the lungs; median values of the difference were 2.8% and 0.5% with and without lymph node metastases in stations 2 or 3, respectively (p = 0.027). Of the ESTRO guideline for the nodal CTV, using the option for geometric expansion might be able to reduce V20 Gy of the lungs in patients with lymph node metastases in stations 2 or 3.

Relationship Between Spatial Distribution Tumor Location and Dosimetric Outcomes in Patients Receiving Definitive Proton Therapy for Locally Advanced Lung Cancer

Intensity Modulated Proton Therapy with Pencil Beam Scanning (IMPT/PBS) has been postulated to have dosimetric benefits, especially for sparing of normal tissues in the treatment of thoracic malignancies. Distinguishing which patients may benefit most from IMPT/PBS treatment has important implications when counseling patients on optimal treatment modality, treatment approval turnaround time, and potential toxicities. We herein present a single institution experience assessing the relationship between spatial distribution of tumor location and dosimetric outcomes in patients receiving definitive IMPT/PBS for locally advanced lung cancer. Consecutive patients treated with IMPT/PBS for locally advanced lung cancer from 2016-2022 at an academic proton center were retrospectively analyzed. Treatment, tumor volume, and patient characteristics were collected. Distance from the posterior pleura to the anterior-most portion of the clinical tumor volume (CTV) of the tumor was measured. A ratio of this distance to the pleura-to-pleura distance at that corresponding lung level was used to classify anterior (>0.7) versus posterior tumors. Dosimetric details including beam angles, dose-volume parameters for the ipsilateral, contralateral, total lung and heart for each patient were recorded. Statistical differences between groups were determined using Wilcoxon Signed Rank test. Pearson's correlation coefficient was used to determine impact of CTV volume and the anterior-most distance of CTV on dosimetric parameters. Fifty-eight patients treated for Stage IIB-IIIC locally advanced lung cancer with a median CTV volume of 258 cc's were identified and included in this retrospective study. Median age was 68 years and there was an equal distribution of male (29, 50%) and female patients (29, 50%) as well as anterior (>0.7) and posterior lying tumors in this cohort. The majority of patients were white (42, 72%) Forty patients (69%) had right sided lung tumors. Median cumulative dose was 61.2 Gy (range 59.4-70 Gy) while median dose per fraction was 2 Gy (range 1.8-2 Gy). When compared to anterior tumors, posterior tumors had a lower Lung V20 (19.1% vs 21.6%, p = 0.1,), V5 (27.6% vs 32.4%, p = 0.03), Mean Lung (9.9 Gy vs 11.7 Gy, p = 0.04), Mean Heart (4.8 Gy vs 6.3 Gy, p = 0.1), and Heart V50 (3.1% vs. 4.6%, p = 0.15). Anterior-most distance of CTV from the posterior pleura was positively correlated with Lung V20 (r = .435, p = 0.001), Lung V5 (r = .390, p = 0.002), Mean Lung (r = .479, p = 0.001), Mean Heart (r = .304, p = 0.020), and Heart V50 (r = .322, p = 0.014). CTV volume was also significantly positively correlated (p <.01) with these parameters. Spatial distribution and treatment volume size are predictive of dosimetric outcomes for locally advanced lung cancer. Posterior lying tumors may derive greater dosimetric advantage when compared to anterior lesions when utilizing IMPT/PBS.

External Validation of 8 Normal Tissue Complication Probability Models for Radiation-Associated Primary Hypothyroidism Using Long-Term Thyroid Function Outcomes

Primary hypothyroidism is a common late complication following neck irradiation. The reported incidences were as high as 20-50% among head and neck cancer survivors. Several normal tissue complication probability models for radiation-associated primary hypothyroidism have been proposed, but none has been externally validated using long-term thyroid function outcome. We undertook a systematic review of the literature and identified 8 distinct normal tissue complication probability (NTCP) models for radiation-associated primary hypothyroidism (6 logistic regression models and 2 nomograms). We retrospectively contoured and reviewed the thyroid gland dosimetry of all consecutive head and neck cancer patients who underwent definitive radiotherapy between January 2013 and December 2015 in two tertiary oncology centers. Patients with abnormal pre-radiotherapy thyroid function were excluded. Thyroid function was monitored at least yearly after radiotherapy. Primary hypothyroidism was defined as serum thyroid-stimulating hormone levels above the upper limit of normal. Euthyroid controls were defined as patients who had normal thyroid function at least 5 years beyond the completion of radiotherapy. Diagnostic properties (sensitivity, specificity and accuracy) of the 8 NTCP models were determined. Discrimination and calibration of the models were assessed using c-statistics, discrimination slopes, calibration curves and Brier score. With a median follow-up of 7.0 years, we identified 216 cases of post-radiation primary hypothyroidism and 120 euthyroid controls within the study period. All four logistic regression models (Boomsma 2012, Rønjom 2013, Shen 2021 and Huang 2021) which were based on mean thyroid dose and thyroid volume demonstrated satisfactory diagnostic performances. The accuracy, c-statistic, discrimination slope and Brier score of these four models were > 0.70 (0.711 - 0.732), > 0.75 (0.763 - 0.765), > 0.20 (0.203 - 0.295) and < 0.20 (0.187 - 0.198), respectively. Calibrations of prediction were excellent at ranges of high predicted probabilities. At ranges of low predicted probabilities, these models underestimated the risk of primary hypothyroidism by 10-20%. Other models or nomograms which utilized alternative radiation dose-volume parameters (e.g., V30, V35 or V50), or without factoring in the variation in thyroid volume, had significantly worse performance in terms of both discrimination and calibration. This large external validation study showed that NTCP models that included thyroid volume and mean thyroid dose had satisfactory performances in predicting long-term thyroid function outcomes following neck irradiation. Refinement is required to optimize calibration in patients deemed at low risk of post-radiation primary hypothyroidism.

The population percentile allowance method for determining systematic spatial error tolerances for temporary intensity modulated brachytherapy.

Multiple approaches are under development for delivering temporary intensity modulated brachytherapy (IMBT) using partially shielded applicators wherein the delivered dose distributions are sensitive to spatial uncertainties in both the applicator position and shield orientation, rather than only applicator position as with conventional high-dose-rate brachytherapy (HDR-BT). Sensitivity analyses to spatial uncertainties have been reported as components of publications on these emerging technologies, however, a generalized framework for the rigorous determination of the spatial uncertainty tolerances of dose-volume parameters is needed. To derive and present the population percentile allowance (PPA) method, a generalized mathematical and statistical framework to evaluate the tolerance of temporary IMBT approaches to spatial uncertainties in applicator position and shield orientation. A mathematical formalism describing geometric applicator position and shield orientation shifts was derived that supports straight and curved applicators and applies to serial and helical rotating shield brachytherapy (RSBT) and direction modulated brachytherapy (DMBT). The PPA method entails defining the percentage of a patient population receiving a given therapy that is, allowed to receive dose-volume errors in the target volume and specified organs at risk of a defined percentage or less, then determining what combinations of applicator position and shield orientation systematic errors would be expected to produce that outcome in the population. The PPA method was applied to the use case of multi-shield helical 169 Yb-based RSBT for cervical cancer, with 45° and 180° shield emission angles. A total of 37 cervical cancer patients were considered in the population, with average (±1standarddeviation) HR-CTV volumes of 79 cm3 ±37 cm3 and optimized baseline treatment plans (no spatial uncertainties applied) created for each patient to meet dose-volume requirements of 85 GyEQD2 (equivalent uniform dose in 2Gy fraction), with D2cc tolerance doses of 90GyEQD2 , 75GyEQD2 , and 75GyEQD2 for bladder, rectum, and sigmoid colon, respectively. For the PPA requirement that 90% of cervical cancer patients receiving multi-shield helical RSBT could have a maximum dose-volume uncertainty of 10% for high-risk clinical target volume (HR-CTV) D90 (minimum dose to hottest 90%) and bladder, rectum, and sigmoid colon D2cc (minimum dose to hottest 2 cm3 ), the tolerance systematic applicator position and shield orientation uncertainties were approximately±1.0mm and±4.25°, respectively. For±1.5mm and±5° systematic applicator position and shield orientation tolerances, 90% of the patients considered would have a maximum dose-volume uncertainty of 12.8% or less. The PPA method was formalized to determine the temporary IMBT spatial uncertainty tolerances that would be expected to result in an allowed percentage of a population of patients receiving relative dose-volume errors above a defined percentage. Multi-shield, helical 169 Yb-based RSBT for cervical cancer was evaluated and tolerances determined, which, if applied on each treatment fraction, would represent an extreme situation. The PPA method is applicable to a variety of temporary IMBT approaches and can be used to rigorously determine the design parameters for the delivery systems such as mechanical driver motor accuracy, shield angle backlash, applicator rotation, and applicator fixation stability.

Clinical implications of dose to functional lung volumes in the trimodality treatment of esophageal cancer

Background Trimodality treatment, i.e., neoadjuvant chemoradiotherapy (nCRT) followed by surgery, for locally advanced esophageal cancer (EC) improves overall survival but also increases the risk of postoperative pulmonary complications. Here, we tried to identify a relation between dose to functional lung volumes (FLV) as determined by 4D-CT scans in EC patients and treatment-related lung toxicity. Materials and methods All patients with EC undergoing trimodality treatment between 2017 and 2022 in UZ Leuven and scanned with 4D-CT-simulation were selected. FLVs were determined based on Jacobian determinants of deformable image registration between maximum inspiration and expiration phases. Dose/volume parameters of the anatomical lung volume (ALV) and FLV were compared between patients with versus without postoperative pulmonary complications. Results of pre- and post-nCRT pulmonary function tests (PFTs) were collected and compared in relation to radiation dose. Results Twelve out of 51 EC patients developed postoperative pulmonary complications. ALV was smaller while FLV10Gy and FLV20Gy were larger in patients with complications (respectively 3141 ± 858mL vs 3601 ± 635mL, p = 0.025; 360 ± 216mL vs 264 ± 139mL, p = 0.038; 166 ± 106mL vs 118 ± 63mL, p = 0.030). No differences in ALV dose-volume parameters were detected. Baseline FEV1 and TLC were significantly lower in patients with complications (respectively 90 ± 17%pred vs 102 ± 20%pred, p = 0.033 and 93 ± 17%pred vs 110 ± 13%pred, p = 0.001), though no other PFTs were significantly different between both groups. DLCO was the only PFT that had a meaningful decrease after nCRT (85 ± 17%pred vs 68 ± 15%pred, p < 0.001) but was not related to dose to ALV/FLV. Conclusion Small ALV and increasing FLV exposed to intermediate (10 to 20 Gy) dose are associated to postoperative pulmonary complications. Changes of DLCO occur during nCRT but do not seem to be related to radiation dose to ALV or FLV. This information could attribute towards toxicity risk prediction and reduction strategies for EC.

Association of radiation dose to cardiac substructures with major ischaemic events following breast cancer radiotherapy.

Patients with left-sided breast cancer receive a higher mean heart dose (MHD) after radiotherapy, with subsequent risk of ischaemic heart disease. However, the optimum dosimetric predictor among cardiac substructures has not yet been determined. This study retrospectively reviewed 2158 women with breast cancer receiving adjuvant radiotherapy. The primary endpoint was a major ischaemic event. The dose-volume parameters of each delineated cardiac substructure were calculated. The risk factors for major ischaemic events and the association between MHD and major ischaemic events were analysed by Cox regression. The optimum dose-volume predictors among cardiac substructures were explored in multivariable models by comparing performance metrics of each model. At a median follow-up of 7.9 years (interquartile range 5.6-10.8 years), 89 patients developed major ischaemic events. The cumulative incidence rate of major ischaemic events was significantly higher in left-sided disease (P = 0.044). Overall, MHD increased the risk of major ischaemic events by 6.2% per Gy (hazard ratio 1.062, 95% confidence interval 1.01-1.12; P = 0.012). The model containing the volume of the left ventricle receiving 25 Gy (LV V25) with the cut-point of 4% presented with the best goodness of fit and discrimination performance in left-sided breast cancer. Age, chronic kidney disease, and hyperlipidaemia were also significant risk factors. Risk of major ischaemic events exist in the era of modern radiotherapy. LV V25 ≥ 4% appeared to be the optimum parameter and was superior to MHD in predicting major ischaemic events. This dose constraint could aid in achieving better heart protection in breast cancer radiotherapy, though a further validation study is warranted.

Improving knowledge-based treatment planning for lung cancer radiotherapy with automatic multi-criteria optimized training plans

Background Knowledge-based planning (KBP) is a method for automated radiotherapy treatment planning where appropriate optimization objectives for new patients are predicted based on a library of training plans. KBP can save time and improve organ at-risk sparing and inter-patient consistency compared to manual planning, but its performance depends on the quality of the training plans. We used another system for automated planning, which generates multi-criteria optimized (MCO) plans based on a wish list, to create training plans for the KBP model, to allow seamless integration of knowledge from a new system into clinical routine. Model performance was compared for KBP models trained with manually created and automatic MCO treatment plans. Material and Methods Two RapidPlan models with the same 30 locally advanced non-small cell lung cancer patients included were created, one containing manually created clinical plans (RP_CLIN) and one containing fully automatic multi-criteria optimized plans (RP_MCO). For 15 validation patients, model performance was compared in terms of dose-volume parameters and normal tissue complication probabilities, and an oncologist performed a blind comparison of the clinical (CLIN), RP_CLIN, and RP_MCO plans. Results The heart and esophagus doses were lower for RP_MCO compared to RP_CLIN, resulting in an average reduction in the risk of 2-year mortality by 0.9 percentage points and the risk of acute esophageal toxicity by 1.6 percentage points with RP_MCO. The oncologist preferred the RP_MCO plan for 8 patients and the CLIN plan for 7 patients, while the RP_CLIN plan was not preferred for any patients. Conclusion RP_MCO improved OAR sparing compared to RP_CLIN and was selected for implementation in the clinic. Training a KBP model with clinical plans may lead to suboptimal output plans, and making an extra effort to optimize the library plans in the KBP model creation phase can improve the plan quality for many future patients.