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Background In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. Methods All patients, including retrospective training ( n  = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n  = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. Results Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25–0.74, p  = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups ( p  = 0.063), with a significant treatment interaction ( p interaction  <  0.001). This trend was also found in the validation cohort with high ( n  = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06–0.51, p  <  0.001) and low ICTOS ( n  = 175, p  = 0.31), with a significant treatment interaction ( p interaction  = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors. Conclusion An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment. Trial registration ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.

Background A dummy run was conducted to ensure the quality of intensity-modulated radiotherapy (IMRT) before registration in a randomized phase III study of elderly patients with newly diagnosed glioblastoma by the Japan Clinical Oncology Group 1910 (JCOG1910). Methods All 41 institutions enrolled in this study were required to report outlining that included gross tumor volume (GTV), clinical target volume (CTV), planning target volume (PTV), and treatment planning for one benchmark case. First, deviations in outlining were evaluated using the Dice similarity coefficient (DSC) and mean distance agreement (MDA), compared to reference targets delineated by the research secretariat. Second, the participating institutions were required to create treatment plans for arms A (40.05 Gy in 15 fractions) and B (25 Gy in 5 fractions) using IMRT techniques. The quality of the outlining and dose-volume criteria for each target and organs at risk were evaluated. Results Six institutions failed to adhere to the protocol and required revision due to insufficient GTV outlining, not considering anatomical barriers for CTV, and modifying PTV against protocols. Compared to the reference outlining, the means and standard deviations of DSC and MDA were 0.37 ± 0.19 and 9.41 ± 3.99 mm for GTV; 0.80 ± 0.08 and 4.31 ± 1.85 mm for CTV; and 0.83 ± 0.05 and 4.23 ± 1.45 mm for PTV, respectively. Regarding dose-volume criteria, 40 of the 41 institutions met the per-protocol limits; only one was within the acceptable limits. Conclusions Several institutions demonstrated deviations in outlining that necessitated revisions. Thus, appropriate feedback and periodic sharing of information with participating institutions is necessary in the upcoming prospective JCOG1910 study.

Purpose Results of a prospective, randomized controlled trial at our institute demonstrate an association between the dose to the left hippocampus and neurocognitive decline post‐radiotherapy for patients with glioblastoma. To minimize the dose to the left hippocampus, a left hippocampus sparing model was created using RapidPlan (RP) and multi‐criteria optimization (MCO). Materials and methods For 147 patients with newly diagnosed glioblastoma treated with volumetric modulated arc therapy (VMAT), the left and right hippocampus were delineated. Ninety‐seven of 147 VMAT plans were used to configure a RP model named HCS1. The remaining 50 VMAT plans were used for the model validation. All 97 plans were replanned with the HCS1 and further optimized using MCO (HCS1+MCO). MCO was used to explore the trade‐off between reducing the left hippocampus mean dose and planning objectives for the targets and other organs‐at‐risk (OAR) for HCS1 plans. These plans were used to create a new model called HCS2. MCO and RP model configuration were done within the Eclipse treatment planning system. Results The final HCS2 model decreased the mean dose to the left hippocampus by 26% compared to clinically treated plans without reducing target coverage for 50 validation data. The mean dose to the left hippocampus decreased from 32.65 Gy in clinically treated plans, 30.45 Gy in HCS1‐generated plans, and 24.04 Gy in HCS2‐generated plans. The mean volume receiving 95% of the prescription dose (V95%) of the planning target volume was 99.08% ± 1.39% in clinically treated plans, 99.03% ± 1.37% in HCS1‐generated plans, and 98.80% ± 1.48% in HCS2‐generated plans. Mean dose to 0.1 cc of the brainstem improved from 45.91 Gy in clinically treated plans to 39.29 Gy in HCS2‐generated plans. Conclusions The RP model and MCO helps to decrease left hippocampus mean dose while maintaining the target volume coverage and OAR sparing comparable to clinically treated plans for glioblastoma patients.

Background Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB). Methods This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter. Discussion This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases. Trial registration The HIPPORAD trial is registered with the German Clinical Trials Registry ( DRKS00004598 , registered 2 June 2016).

Background Esophageal carcinoma is the eighth most common cancer in the world. Volumetric‐modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small‐spot intensity‐modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small‐spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects. Methods 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small‐spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase‐averaged 4D‐CT's. The dose‐volume‐histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank‐sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose. Results In the nominal scenario, small‐spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and D0.03cm3, liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, D2cm3, and D5%‐D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations. The small‐spot IMPT plans still met the standard clinical requirements after interplay effects were considered. Conclusions Small‐spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small‐spot IMPT for the treatment of distal esophageal carcinoma.

Background Recurrent ovarian cancer is often treated with chemotherapy, but many patients experience multiple recurrences with progressively shorter intervals and poorer prognosis. Repeated chemotherapy reduces patients’ quality of life. Stereotactic Ablative Radiation Therapy for Recurrent Ovarian Cancer (SABR-ROC) (KGOG3064/KROG 2204) is an ongoing trial investigating the clinical efficacy of stereotactic ablative radiation therapy (SABR) for recurrent ovarian cancer. This study aimed to assess treatment planning consistency and protocol adherence in a prospective, randomized, multicenter phase III trial. Methods In this dummy run study of a prospective, randomized, multicenter phase III trial (SABR-ROC), we examined the variability in target delineation, dose prescription, and treatment planning among 10 centers participating in the SABR-ROC trial. Four representative cases, each presenting with different anatomical sites and treatment challenges, were selected for evaluation. Target volume consistency was measured using the Dice similarity coefficient, and treatment plans were reviewed to follow predefined goals and constraints in the protocol. Results Overall agreement in target delineation was low, with mean Dice similarity coefficients of 0.278 and 0.255 for gross tumor volume and planning target volume, respectively. Consistency was higher for cases involving lymph node and lung metastases but significantly lower for intraperitoneal and liver seeding metastases due to challenges in target delineation. Treatment plans generally adhered to protocol dose prescriptions, with minor deviations in planning target volume coverage, particularly in cases with multiple small metastases. Deviations from organ-at-risk constraints frequently occurred in cases involving small bowel proximity. Conclusions This study highlights the challenges in standardizing SABR for recurrent ovarian cancer, particularly in achieving a consensus on target delineation and balancing treatment efficacy with organ-at-risk safety. Clinician discretion remains essential in complex cases. The insights from this study will guide the development of standardized protocols to improve outcomes and reduce adverse effects in patients with recurrent ovarian cancer. Trial registration This trial was registered with ClinicalTrials.gov under the identifier NCT05444270 on June 29, 2022.

Background and purpose The aim of this study is to evaluate the effectiveness of a cervical muscle training intervention in decreasing setup errors in patients head and neck cancer (HNC) undergoing radiotherapy (RT). Materials and methods HNC patients opting for RT at our center. The patients were randomly allocated to either the muscle training group or the control group in a 1:1 ratio. The magnitude of the setup error was measured at the levels of the clivus, C4 and C7 vertebrae respectively. The Van Herk formula was used to determine appropriate planning target volume (PTV) margins. (Trial Registration: ChiCTR2000041009, registration date: 12/16/2020) Results A total of 221 patients were analyzed, with 109 assigned to the muscle training group and 112 enrolled in the control group. Compared with the control group, the setup errors in the X and Z direction of the clivus and the Z direction of C4 and C7 in the muscle training group were significantly lower ( p  = 0.031, < 0.001, < 0.001, < 0.001 respectively). The required PTV margins in the Z direction increased from 2.13 mm in the clivus to 3.63 mm in C7 in the muscle training group and from 2.89 mm in the clivus to 4.37 mm in C7 in the control group. Multivariate linear regression analysis demonstrated that the impact of neck muscle training, weight fluctuation, and cervical curvature on the setup error in the Z direction at C7 differed significantly ( p  = 0.000, 0.001, and 0.008, respectively). Conclusion Neck muscle training can reduce setup errors and PTV margins in the anterior-posterior direction in patients undergoing RT for HNC.

Purpose This study aims to develop an algorithm to predict gamma passing rate (GPR) in the volumetric‐modulated arc therapy (VMAT) technique. Materials and methods A total of 118 clinical VMAT plans, including 28 mediastina, 25 head and neck, 40 brains intensity‐modulated radiosurgery, and 25 prostate cases, were created in RayStation treatment planning system for Edge and TrueBeam linacs. In‐house scripts were developed to compute Modulation indices such as plan‐averaged beam area (PA), plan‐averaged beam irregularity (PI), total monitor unit (MU), leaf travel/arc length, mean dose rate variation, and mean gantry speed variation. Pretreatment verifications were performed on ArcCHECK phantom with SNC software. GPR was calculated with 3%/2 mm and 10% threshold. The dataset was randomly split into a training (70%) and a test (30%) dataset. A random forest regression (RFR) model and support vector regression (SVR) with linear kernel were trained to predict GPR using the complexity metrics as input. The prediction performance was evaluated by calculating the mean absolute error (MAE), R2, and root mean square error (RMSE). Results RMSEs at γ 3%/2 mm for RFR and SVR were 1.407 ± 0.103 and 1.447 ± 0.121, respectively. MAE was 1.14 ± 0.084 for RFR and 1.101 ± 0.09 for SVR. R2 was equal to 0.703 ± 0.027 and 0.689 ± 0.053 for RFR and SVR, respectively. GPR of 3%/2 mm with a 10% threshold can be predicted with an error smaller than 3% for 94% of plans using RFR and SVR models. The most important metrics that had the greatest impact on how accurately GPR can be predicted were determined to be the PA, PI, and total MU. Conclusion In terms of its prediction values and errors, SVR (linear) appeared to be comparable with RFR for this dataset. Based on our results, the PA, PI, and total MU calculations may be useful in guiding VMAT plan evaluation and ultimately reducing uncertainties in planning and radiation delivery.

BackgroundPublished treatment technique comparisons for postoperative left-sided whole breast irradiation (WBI) with deep-inspiration breath-hold (DIBH) are scarce, small, and inconclusive. In this study, fully automated multi-criterial plan optimization, generating a single high-quality, Pareto-optimal plan per patient and treatment technique, was used to compare for a large patient cohort 1) intensity modulated radiotherapy (IMRT) with two tangential fields and 2) volumetric modulated arc therapy (VMAT) with two small tangential subarcs.Materials and methodsForty-eight randomly selected patients recently treated with DIBH and 16 × 2.66 Gy were included. The optimizer was configured for the clinical planning protocol. Comparisons between IMRT and VMAT included dosimetric plan parameters, estimated excess relative risks (ERR) for toxicities, delivery times, MUs, and deliverability accuracy at a linac.ResultsThe automatically generated IMRT and VMAT plans applied in this study were similar or higher in quality than the manually generated clinical plans. For equal PTVin V95% (98.4 ± 0.9%), VMAT had significant advantages compared to IMRT regarding breast dose homogeneity and doses in heart and ipsilateral lung, at the cost of some minor deteriorations for contralateral breast (few cases with larger deteriorations) and lung. Conformality improved from 1.38 to 1.18 (p < 0.001). With VMAT, ERR for major coronary events and ipsilateral lung tumors were reduced by 3% (range: −1–12%) and 16% (range: −3–38%), respectively. MUs and delivery times were higher for VMAT. There were no statistical differences in γ passing rates.ConclusionFor WBI in conservative therapy of left-sided breast patients treated with DIBH, VMAT with two tangential subarcs was generally dosimetrically superior to IMRT with two tangential static fields. Results need confirmation by robustness analyses.

Purpose To compare dosimetric performance of volumetric‐modulated arc therapy (VMAT) and small‐spot intensity‐modulated proton therapy for stage III non‐small‐cell lung cancer (NSCLC). Methods and Materials A total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity‐modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D‐CTs. The dose‐volume‐histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test. Results Compared with VMAT, IMPT delivered significantly lower cord Dmax, heart Dmean, and lung V5 Gy[RBE] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean, but were statistically worse in CTV dose coverage, cord Dmax, lung Dmean, and V5 Gy[RBE]. Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered. Conclusions Small‐spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients.