Primary Clinical Target Volume Research Articles

Long-term Outcomes Following Individualized Elective Primary Tumor CTV Delineation Based on Stepwise Spread Patterns of Nasopharyngeal Carcinoma Treated with Intensity-modulated Radiotherapy.

Our institution has developed an individualized elective primary tumor clinical target volume (CTVp) delineation protocol for nasopharyngeal carcinoma (NPC) based on stepwise tumor spread patterns in intensity-modulated radiotherapy (IMRT) for over ten years. Herein, we report the long-term efficacy and toxicities in NPC patients treated under this protocol. A total of 7,262 histologically proven, nonmetastatic NPC patients treated with IMRT following this individualized delineation protocol were retrospectively evaluated. The 5-year rates for local relapse-free survival (LRFS), regional relapse-free survival (RRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated. Dose-volume histogram (DVH) parameters for patients with local relapse were compared to those of propensity score-matched (PSM) without local relapse. Dosimetric comparisons of our delineation protocol with the 2018 International Guideline (2018-IG) were conducted on representative early- and advanced-stage NPC cases. The 5-year LRFS, RRFS, DMFS, PFS and OS were 93.6%, 94.4%, 86.8%, 77.8%, and 86.0%, respectively. 92.3% of local relapses and 86.0% of regional relapses occurred within the 95% isodose lines and were considered GTV in-field failures. No significant differences in DVH parameters were observed between the local relapse group and the propensity score-matched non-relapse group. Compared with the 2018-IG, our contouring protocol resulted in a 58.4% and 48.3% reduction in PTV70, and an 80.8% and 62.8% reduction in PTV60 for early and advanced-stage disease, respectively. Late grade 3 toxicities included ototoxicity (1.8%), xerostomia (0.2%), dysphagia (0.2%), temporal lobe injury (0.2%), and trismus (0.1%). Individualized elective CTVp delineation based on the stepwise spread patterns of nasopharyngeal carcinoma achieved excellent long-term outcomes and reduced the irradiated volumes at equivalent dose levels compared to the 2018-IG.

First Implementation of Full-Workflow Automation for Online Adaptive Radiotherapy of Nasopharyngeal Carcinoma

The aim of this work is to established the technical characteristics and implementation procedures of an artificial intelligence (AI)-powered radiotherapy workflow that enables full-process automation for online adaptive radiotherapy (ART); and evaluate its feasibility and performance implemented for ART of nasopharyngeal carcinoma (NPC). This single center, prospective study has been approved by the ethical committee of the institution. The online ART workflow was developed based on a CT-integrated linear accelerator. During the course of radiotherapy, the patient underwent daily pre-treatment fan-beam CT (FBCT) scan. Then the FBCT was automatically registered to the original planning CT and used to assess the need for the patient to implement ART according to radiation oncologist's discretionary. The online ART workflow incorporates critical radiotherapy procedures from re-simulation, auto-segmentation by integrating image fusion and deep learning method, auto-replanning, beam delivery, and in vivo quality assurance (QA) into one scheme, while the patient is on the treatment couch during the whole process. From 2th April 2022 to 5th January 2023, 20 patients with newly-diagnosed, non-metastatic NPC were enrolled in this study. Only one-time online ART was performed for each patient, because that the appropriate timing for triggering online ART was explored in parallel with this study. According to radiation oncologists' discretionary, the median fraction for performing online ART was at 21 fractions (interquartile range, 19-24 fractions). All patients were well tolerated and successfully completed the treatment. For tumor targets contouring, minor revisions were required for automated contours of the primary gross tumor volume (GTVp) and clinical target volumes (CTVs, including CTV1 and CTV2), with the mean DSC between before and after revision of 0.91±0.042, 0.94 ± 0.042 and 0.91 ± 0.061, respectively; and much more revisions for the automated contours of cervical lymph nodes GTV (GTVn), with the mean DSC of 0.74 ± 0.28. The automated contours of normal tissues were clinically acceptable with little modifications. Median time consuming for auto-segmentation and revision was 9.5 minutes (min). For treatment planning, 18 automated plans (90%) were passed at their first auto-optimization and two plans (10%) were passed after further optimization of the dose coverage of CTVs by physicist; and the median time consuming for auto-planning was 6.2 min. Time consuming for other procedures were as follows: re-simulation, 2.3 min; plan evaluation, 3.3 min; beam delivery, 4.6 min; and the duration of the entire process was 25.9 min, range from 19.4 min to 32.5 min. We successfully established an AI-powered online ART workflow for adaptive radiotherapy of NPC, and confirmed that current auto-segmentation and auto-replanning methods are powered enough to support the clinical application of its online ART.

Plan robustness evaluation strategies in whole-pelvic proton therapy for high-risk prostate cancer patients within a randomised clinical trial

Background Inter-fractional anatomical changes challenge robust delivery of whole-pelvic proton therapy for high-risk prostate cancer. Pre-treatment robust evaluation (PRE) takes uncertainties in isocenter shifts and distal beam edge in treatment plans into account. Using weekly control computed tomography scans (cCTs), the aim of this study was to evaluate the PRE strategy by comparing to an off-line during-treatment robust evaluation (DRE) while also assessing plan robustness with respect to protocol planning constraints. Material and methods Treatment plans and cCTs from ten patients included in the pilot phase of the PROstate PROTON Trial 1 were analysed. Treatment planning followed protocol guidelines with 78 Gy to the primary clinical target volume (CTVp) and 56 Gy to the elective target (CTVe) in 39 fractions. Recalculations of the treatment plans were performed for a total of 64 cCTs and dose/volume measures corresponding to clinical constraints were evaluated for this DRE against the simulated scenario interval from the PRE. Results Of the 64 cCTs, 59 showed DRE CTVp measures within the robustness range from the PRE; this was also the case for 39 of the cCTs for the CTVe measures. However, DRE CTVe coverage was still within constraints for 57 of the 64 cCTs. DRE dose/volume measures for CTVp fulfilled target coverage constraints in 59 of 64 cCTs. All DRE measures for the rectum, bladder, and bowel were inside the PRE range in 63, 39, and 31 cCTs, respectively. Conclusion The PRE strategy predicted the DRE scenarios for CTVp and rectum. CTVe, bladder, and bowel showed more complex anatomical variations than simulated by the PRE isocenter shift. Both original and recalculated nominal treatment plans showed robust treatment delivery in terms of target coverage.

Impact of consensus guidelines on delineation of primary tumor clinical target volume (CTVp) for head and neck cancer: Results of a national review project

Background and purposeA significant interobserver variability (IOV) for clinical target volume of the primary tumor (CTVp) delineation was shown in a previous national review project. Since then, international expert consensus guidelines (CG) for the delineation of CTVp were published. The aim of this follow-up study was to 1) objectify the extent of implementation of the CG, 2) assess its impact on delineation quality and consistency, 3) identify any remaining ambiguities. Materials and methodsAll Belgian RT departments were invited to complete an online survey and submit CTVp for 5 reference cases. Organs at risk and GTV of the primary tumor were predefined. Margins, volumes, IOV between all participating centers (IOVall) and IOV compared to a reference consensus delineation (IOVref) were calculated and compared to the previous analysis. A qualitative analysis was performed assessing the correct interpretation of the CG for each case. Results17 RT centers completed both survey and delineations, of which 88% had implemented CG. Median DSCref for CTVp_total was 0.80–0.92. IOVall and IOVref improved significantly for the centers following CG (p = 0.005). IOVref for CTVp_high was small with a DSC higher than 0.90 for all cases. A significant volume decrease for the CTVp receiving 70 Gy was observed. Interpretation of CG was more accurate for (supra)glottic carcinoma. 60% of the radiation oncologists thinks clarification of CG is indicated. ConclusionImplementation of consensus guidelines for CTVp delineation is already fairly advanced on a national level, resulting in significantly increased delineation uniformity. The accompanying substantial decrease of CTV receiving high dose RT calls for caution and correct interpretation of CG. Clarification of the existing guidelines seems appropriate especially for oropharyngeal and hypopharyngeal carcinoma.

Feasibility and Clinical Acceptability of Automation-Assisted 3D Conformal Radiotherapy Planning for Patients With Cervical Cancer in a Resource-Constrained Setting.

The Ocean Road Cancer Institute (ORCI) in Tanzania began offering 3D conformal radiation therapy (3DCRT) in 2018. Steep learning curves, high patient volume, and a limited workforce resulted in long radiation therapy (RT) planning workflows. We aimed to establish the feasibility of implementing an automation-assisted cervical cancer 3DCRT planning system. We performed chart abstractions on 30 patients with cervical cancer treated with 3DCRT at ORCI. The Radiation Planning Assistant (RPA) generated a new automated set of contours and plans on the basis of anonymized computed tomography images. Each were assessed for edit time requirements, dose-volume safety metrics, and clinical acceptability by two ORCI physician investigators. Dice similarity coefficient (DSC) agreement analysis was conducted between original and new contour sets. The average time to manually develop treatment plans was 7 days. Applying RPA, automated same-day contours and plans were developed for 29 of 30 patients (97%). Of the 29 evaluable contours, all were approved with <2 minutes of edit time. Agreement between clinical and RPA contours was highest for the rectum (median DSC, 0.72) and bladder (DSC, 0.90). Agreement was lower with the primary tumor clinical target volume (CTVp; DSC, 0.69) and elective nodal clinical target volume (CTVn; DSC, 0.63). All RPA plans were approved with <4 minutes of edit time. RPA target coverage was excellent, covering the CTVp with median V45 Gy 100% and CTVn with median V45 Gy 99.9%. Automation-assisted 3DCRT contouring yielded high levels of agreement for normal structures. The RPA met all planning safety metrics and sustained high levels of clinical acceptability with minimal edit times. This tool offers the potential to significantly decrease RT planning timelines while maintaining high-quality RT delivery in resource-constrained settings.

CBCT-based deformable dose accumulation of external beam radiotherapy in cervical cancer

Background: Delivered radiotherapy doses do not exactly match those planned for a course of treatment, largely due to inter-fraction changes in anatomy. In this study, accumulated delivered dose was calculated for a sample of cervical cancer patients, by deformably registering daily cone beam computed tomography (CBCT) images to the planning computed tomography (CT) scan. Planned and accumulated doses were compared for the clinical target volume (CTV), bladder, and rectum. Material and Methods: For 10 patients receiving 45 Gy in 25 fractions of external beam radiotherapy, daily dose distributions were calculated on CBCT. These images were deformed onto the planning CT and the dose was accumulated using Velocity 4.1 (Varian Medical Systems, Palo Alto, USA). The quality of deformable image registration was evaluated visually and by calculating Dice similarity coefficients and mean distance to agreement. Results: V95%>99% was achieved for the primary CTV in 9/10 patients for the planned dose distribution and 7/10 patients for the accumulated dose distribution. Primary CTV coverage by 95% of the prescription dose was reduced in one patient, due to an increase in anterior-posterior separation. Comparison of planned and accumulated dose volume histograms (DVHs) for the bladder and rectum found agreement within 5% at low and intermediate doses, but differences exceeded 20% at higher doses. Direct addition of CBCT DVHs was seen to be a poor estimate for the accumulated DVH at higher doses. Conclusion: Computation of delivered radiotherapy dose that accounts for inter-fraction anatomical changes is important for establishing dose-effect relationships. Updating delivered dose distributions after each fraction would support informed clinical decision making on any potential treatment interventions.

Automated Robust Planning for IMPT in Oropharyngeal Cancer Patients Using Machine Learning

The aim of this study was to evaluate an automated treatment planning method for robustly optimized intensity modulated proton therapy (IMPT) plans for oropharyngeal carcinoma patients and to compare the results with manually optimized robust IMPT plans. An atlas regression forest based machine learning (ML) model for dose prediction was trained on CT scans, contours and dose distributions of robust IMPT plans of 88 oropharyngeal cancer patients (OCP). The ML model was combined with a robust voxel and dose volume histogram based dose mimicking optimization algorithm for 21 perturbed scenarios to generate a machine deliverable plan from the predicted dose distribution. Machine learning optimization (MLO) configuration was performed using a cross-validation approach with 3 × 8 tuning patients and comprised of adjustments to the mimicking optimization, to generate higher quality MLO plans. Independent testing of the MLO algorithm was performed with another 25 patients. Plan quality of clinical and MLO plans was evaluated by the clinical target volume (D98% voxel-wise minimum dose >94%), organ at risk (OAR) doses and the normal tissue complication probability (NTCP) (sum (Σ) of grade-2 and grade-3 dysphagia and xerostomia). Adequate robust target coverage was achieved in 24/25 clinical plans and in 23/25 MLO plans in the primary clinical target volume (CTV). In the elective CTV, 22/25 clinical plans and 24/25 MLO plans passed the robust target coverage evaluation threshold. The MLO average Σgrade 2 and Σgrade 3 NTCPs were comparable to the clinical plans (Σgrade 2 NTCPs: clinical 47.5% vs MLO 48.4%, Σgrade 3 NTCPs: clinical 11.9% vs MLO 12.3%). Significant increases in OAR average doses in MLO plans were found in the pharynx constrictor muscles (163 cGy, p=0.002) and cervical esophagus (265 cGy, p=0.002). The MLO plans were created within 45 min. This study showed that automated MLO planning is able to generate robustly optimized MLO plans with quality comparable to clinical plans in OCP.

Understanding the Benefit of Magnetic Resonance-guided Adaptive Radiotherapy in Rectal Cancer Patients: a Single-centre Study

AimsNeoadjuvant chemoradiotherapy followed by surgery is the mainstay of treatment for patients with rectal cancer. Standard clinical target volume (CTV) to planning target volume (PTV) margins of 10 mm are used to accommodate inter- and intrafraction motion of target. Treating on magnetic resonance-integrated linear accelerators (MR-linacs) allows for online manual recontouring and adaptation (MRgART) enabling the reduction of PTV margins. The aim of this study was to investigate motion of the primary CTV (CTVA; gross tumour volume and macroscopic nodes with 10 mm expansion to cover microscopic disease) in order to develop a simultaneous integrated boost protocol for use on MR-linacs. Materials and methodsPatients suitable for neoadjuvant chemoradiotherapy were recruited for treatment on MR-linac using a two-phase technique; only the five phase 1 fractions on MR-linac were used for analysis. Intrafraction motion of CTVA was measured between pre-treatment and post-treatment MRI scans. In MRgART, isotropically expanded pre-treatment PTV margins from 1 to 10 mm were rigidly propagated to post-treatment MRI to determine overlap with 95% of CTVA. The PTV margin was considered acceptable if overlap was >95% in 90% of fractions. To understand the benefit of MRgART, the same methodology was repeated using a reference computed tomography planning scan for pre-treatment imaging. ResultsIn total, nine patients were recruited between January 2018 and December 2020 with T3a-T4, N0–N2, M0 disease. Forty-five fractions were analysed in total. The median motion across all planes was 0 mm, demonstrating minimal intrafraction motion. A PTV margin of 3 and 5mm was found to be acceptable in 96 and 98% of fractions, respectively. When comparing to the computed tomography reference scan, the analysis found that PTV margins to 5 and 10 mm only acceptably covered 51 and 76% of fractions, respectively. ConclusionPTV margins can be reduced to 3–5 mm in MRgART for rectal cancer treatment on MR-linac within an simultaneous integrated boost protocol.

ECOG-ACRIN Guideline for Contouring and Treatment of Early Stage Anal Cancer Using IMRT/IGRT

PurposePrevious anal cancer guidelines delineate target volumes similarly for all patients with squamous cell carcinoma of the anal canal and/or perianal skin (SCCA), regardless of disease stage. The purpose of this guideline is to provide customized radiation treatment recommendations for early stage (T1-2 N0 M0) anal cancer treated with intensity modulated and image guided radiation therapy (RT). Methods and MaterialsA contouring atlas and radiation treatment recommendations for the ongoing, randomized phase II trial of deintensified chemoradiation for early stage SCCA (EA2182) was created by an expert panel of radiation oncologists. A literature search was conducted to update and expand these recommendations into a guideline for routine clinical use. ResultsFor the majority of cases, we recommend treatment in the supine, frog leg position with the use of a customized immobilization device and daily image guided RT to ensure optimal bone and soft tissue alignment. Vaginal dilators can be used daily during RT to maximize genitalia sparing. We recommend use of a 10-mm margin on the gross tumor plus including the anal complex to create the primary clinical target volume. To define the elective lymph node clinical target volume, we recommend starting with a 7-mm expansion on blood vessels, but then further refining these volumes based on the anatomic location. A 5- to 10-mm planning target volume (PTV) margin is suggested based on institutional setup and patient-specific factors. When using a simultaneous integrated boost technique, a dose of 50.4 Gy to primary PTV and 42 Gy to lymph node PTV, both delivered over 28 fractions, with chemotherapy is appropriate for early stage anal cancer. ConclusionsThis guideline provides anatomic, clinical, and technical instructions to guide radiation oncologists in the planning and delivery of intensity modulated and image guided RT for early stage SCCA.

Radiation-Induced Toxicity Risks in Photon Versus Proton Therapy for Synchronous Bilateral Breast Cancer.

PurposeThis study compares photon and proton therapy plans for patients with synchronous bilateral early breast cancer and estimates risks of early and late radiation-induced toxicities.Materials and MethodsTwenty-four patients with synchronous bilateral early breast cancer receiving adjuvant radiation therapy using photons, 3-dimensional conformal radiation therapy or volumetric modulated arc therapy, were included and competing pencil beam scanning proton therapy plans were created. Risks of dermatitis, pneumonitis, acute esophageal toxicity, lung and breast fibrosis, hypothyroidism, secondary lung and esophageal cancer and coronary artery events were estimated using published dose-response relationships and normal tissue complication probability (NTCP) models.ResultsThe primary clinical target volume V95% and/or nodal clinical target volume V90% were less than 95% in 17 photon therapy plans and none of the proton plans. Median NTCP of radiation dermatitis ≥ grade 2 was 18.3% (range, 5.4-41.7) with photon therapy and 58.4% (range, 31.4-69.7) with proton therapy. Median excess absolute risk (EAR) of secondary lung cancer at age 80 for current and former smokers was 4.8% (range, 0.0-17.0) using photons and 2.7% (range, 0.0-13.6) using protons. Median EAR of coronary event at age 80, assuming all patients have preexisting cardiac risk factors, was 1.0% (range, 0.0-5.6) with photons and 0.2% (range, 0.0-1.3) with protons.ConclusionProton therapy plans improved target coverage and reduced risk of coronary artery event and secondary lung cancer while increasing the risk of radiation dermatitis.

Radiomic Analysis of Primary GTV and CTV for Prediction of Extranodal Extension Using Diagnostic CT Images in Patients With Oropharyngeal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Prediction of extranodal extension (ENE) status of the involved lymph nodes has been shown to be an important factor in the prognosis and treatment of patients with Oropharyngeal Squamous Cell Carcinomas (OPSCC). Official diagnosis of ENE occurs pathologically at the time of surgery, and typically necessitates aggressive adjuvant treatment with radiation and concurrent chemotherapy. Due to higher toxicity with trimodality therapy, definitive chemoradiation can be a preferred treatment option up front instead of surgery if there is high clinical suspicion of ENE. This study investigates the potential value of radiomic features extracted from pre-treatment primary gross tumor volume (GTV) and clinical target volume (CTV) on diagnostic contrast enhanced Computed Tomography (CE-CT) images for prediction of ENE in patients with OPSCC. <h3>Materials/Methods</h3> For this study we identified 26 patients with pathologically confirmed OPSCC who went on to receive surgery and neck nodal dissection. Out of this group 13 were p16 positive, 13 were p16 negative, 7 were pathologic ENE positive, and 19 pathologic ENE negative. We contoured the primary tumor GTV on their pre-surgery CE-CT and added a 1 cm to create the CTV for radiomic analysis. For each patient, two sets of IBSI (Image Biomarker Standardization Initiative) validated radiomic features (N = 192 features from 11 different feature categories) were extracted from primary GTV and CTV on the diagnostic CE-CT images. Levene and Kolmogorov-Smirnov's (KS, <i>P</i> < 0.05) tests with confidence level of 95% along with absolute biserial correlation (|BSC|) with a threshold of > 0.2 were used to statistically reveal significant associations between ENE status and radiomics features. The Belsley collinearity diagnostics test was applied on the discriminant radiomic features for removing highly correlated features. Eight different Generalized-Linear Models (GLMs) were trained and tested using each individual feature along with two combined feature sets (combined discriminant features extracted from GTV and CTV). Balanced Accuracy Score (BAS), Positive predictive and negative predictive values (<b>PPV</b> and <b>NPV</b>, respectively) were used to evaluate the performance of the classifiers. <h3>Results</h3> Four GTV-based radiomic features and two CTV-based radiomic features (both from textural feature categories) were found to be statistically significant discriminators between the two ENE cohorts. Performances for prediction of the ENE for the two classifiers trained with the combined feature sets were: GTV-based GLM: BAS/PPV/NPV = 0.765/0.724/0.805 and CTV-based GLM: 0.875/0.928/0.822. Results imply that the CTV-based features have greater predictive value compared to GTV-based features for characterization of ENE. <h3>Conclusion</h3> This pilot study, albeit subject to confirmation in a larger patient population, suggests potential for the use of radiomics-based signatures extracted from the primary tumor for prediction of ENE in patients with OPSCC.

Recurrence and Quality-of-Life Following Involved Node Radiotherapy for Head and Neck Squamous Cell Carcinoma: Initial Results From the Phase II INRT-Air Trial

Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy (RT). However, ENI is often responsible for the majority of the dose to the salivary glands and swallowing organs-at-risk (OAR), and recent prospective studies have supported reduced elective neck volume and dose. Moreover, with sensitive staging studies and artificial intelligence (AI), our ability to identify occult lymphadenopathy is greatly improving. In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity modulated radiation therapy.Patients with newly-diagnosed squamous cell carcinoma of the oropharynx, larynx and hypopharynx were eligible for enrollment, excluding stage I-II glottic larynx. Each LN was characterized as involved or suspicious based on CT (e.g., cross-sectional size, enhancement pattern) and PET criteria and an in-house AI-based classification model. Gross disease and the primary clinical target volume were irradiated to 70 and 63 Gy in 35 fractions, respectively, and suspicious LN were treated to 66.5 Gy. Concurrent chemotherapy was required for stage T3N0-1 and IVA/B patients. The primary endpoint of the study was risk of solitary elective volume LN recurrence (i.e., LN recurrence in a classic ENI field without synchronous in-field or distant failure), with secondary endpoints including patterns-of-failure and patient reported outcomes.Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer (88% p16+). In total, 10% and 90% of patients were treated with accelerated RT and chemoRT, respectively. Average contralateral/ipsilateral mean parotid and contralateral submandibular doses were 11.9/18.4 Gy and 34.1 Gy, respectively, and average mean larynx/inferior constrictor/esophagus doses for oropharynx patients were 18.9/12.2/6.7 Gy. With a median follow-up of 12.8 months for surviving patients, there have been no solitary elective volume LN recurrences. Four patients have died from unrelated causes, and one died from in-field local progression. Gastrostomy was placed in 14 (21%), with median removal after 2.8 months for disease-free patients; only one patient is still dependent. Grade 1/2 dermatitis was seen in 90%/10% patients. There was no significant difference in MDADI score between baseline and months 3 and 6 post-RT; for patients with baseline MDADI score > 75, the scores at 3/6 months were 84/83.Preliminary results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable OAR dosimetry and promising quality-of-life outcomes. Longer follow-up is needed to confirm these results.

Continuing Education Needs Identified During the Initial Experience of Delivering 3D Conformal Radiotherapy for Cervical Cancer Patients in Tanzania

In resource-limited settings where experience with 3D conformal radiation therapy (3DCRT) is still growing, review of simulation CTs and radiation therapy plans may illuminate topics for continuing education. We conducted a review of an early cohort of cervical cancer patients treated with 3DCRT in Tanzania to identify education needs that may be generalizable to similar resource-limited settings.In Tanzania, 3DCRT capabilities began in August 2018. A retrospective review of 30 consecutive patients who received definitive whole pelvis 3DCRT for cervical cancer from 2019 to 2020 was conducted after IRB approval. Each patient's simulation CT was evaluated for evidence of advanced disease not detected on initial diagnostic work-up, including pelvic or para-aortic lymphadenopathy (LAD) defined as axial dimension > = 1 cm. An independent set of contours was generated according to United States national consensus guidelines. DICE similarity coefficient (DSC) agreement analysis was conducted between contours. As non-systematic variations in planning target volume (PTV) labelling, summations, and expansions precluded direct comparisons, only clinical target volume (CTV) contours were compared in this analysis. Clinically treated 3DCRT plans were evaluated using original and consensus-based contours, and dosimetric coverage was compared using Wilcoxon signed-rank testing.Simulation CT was the sole means of pre-treatment cross-sectional abdominopelvic imaging in 24/30 patients (80%). The pre-simulation clinical stages were FIGO IB (n = 6), IIA (n = 10), IIB (n = 12), IIIA (n = 1), and IVA (n = 1). Simulation CT upstaged 20 of 30 patients (66.7%) to IIIC1 or IIIC2 disease, identifying eight patients with para-aortic LAD and 13 patients with pelvic LAD. Agreement analysis between clinical and consensus-based contours revealed high agreement in the primary CTV (DSC median 0.83, IQR 0.68 - 0.87), bladder (0.93, IQR 0.88 - 0.95), and femur (0.86) contours, but lower agreement in lymph node CTV (CTVn) contours (DSC 0.59, IQR 0.46 - 0.67). The median volume of clinical-CTVn covered by 45 Gy was 99.7% (IQR 97.5 - 100) while the median volume of consensus-CTVn covered by 45 Gy was 83.3% (IQR 80.1 - 90.1) (P < 0.001). The most frequently undercovered regions were the superior and inferior pre-sacral nodal regions.In resource-limited settings, early case review after 3DCRT initiation may reveal key elements in radiation planning that can guide continuing education topics. In our setting, high yield interventions include systematic evaluation of pelvic and para-aortic LAD on simulation CTs, educational refreshers about nodal contouring, and development of resource-appropriate treatment paradigms when advanced nodal disease is detected.

Automatic Segmentation Using Deep Learning to Enable Online Dose Optimization During Adaptive Radiation Therapy of Cervical Cancer

This study investigated deep learning models for automatic segmentation to support the development of daily online dose optimization strategies, eliminating the need for internal target volume expansions and thereby reducing toxicity events of intensity modulated radiation therapy for cervical cancer. The cervix-uterus, vagina, parametrium, bladder, rectum, sigmoid, femoral heads, kidneys, spinal cord, and bowel bag were delineated on 408 computed tomography (CT) scans from patients treated at MD Anderson Cancer Center (n = 214), Polyclinique Bordeaux Nord Aquitaine (n = 30), and enrolled in a Medical Image Computing & Computer Assisted Intervention challenge (n= 3). The data were divided into 255 training, 61 validation, 62 internal test, and 30 external test CT scans. Two models were investigated: the 2-dimensional (2D) DeepLabV3+ (Google) and 3-dimensional (3D) Unet in RayStation (RaySearch Laboratories). Three intensity modulated radiation therapy plans were generated on each CT of the internal and external test sets using either the manual, 2D model, or 3D model segmentations. The dose constraints followed the External beam radiochemotherapy and MRI based adaptive BRAchytherapy in locally advanced CErvical cancer (EMBRACE) II protocol, with reduced margins of 5 and 3 mm for the target and nodal planning target volume. Geometric discrepancies between the manual and predicted contours were assessed using the Dice similarity coefficient (DSC), distance-to-agreement, and Hausdorff distance. Dosimetric discrepancies between the manual and model doses were assessed using clinical indices on the manual contours and the gamma index. Interobserver variability was assessed for the cervix-uterus, parametrium, and vagina for the definition of the primary clinical target volume (CTVT) on the external test set. Average DSCs across all organs were 0.67 to 0.96, 0.71 to 0.97, and 0.42 to 0.92 for the 2D model and 0.66 to 0.96, 0.70 to 0.97, and 0.37 to 0.93 for the 3D model on the validation, internal, and external test sets. Average DSCs of the CTVT were 0.88 and 0.81 for the 2D model and 0.87 and 0.82 for the 3D model on the internal and external test sets. Interobserver variability of the CTVT corresponded to a mean (range) DSC of 0.85 (0.77-0.90) on the external test set. On the internal test set, the doses from the 2D and 3D model contours provided a CTVT V42.75 Gy >98% for 98% and 91% of the CT scans, respectively. On the external test set, these percentages were increased to 100% and 93% for the 2D and 3D models, respectively. The investigated models provided auto-segmentation of the cervix anatomy with similar performances on 2 institutional data sets and reasonable dosimetric accuracies using small planning target volume margins, paving the way to automatic online dose optimization for advanced adaptive radiation therapy strategies.

Head and neck IMPT probabilistic dose accumulation: Feasibility of a 2 mm setup uncertainty setting

ObjectiveTo establish optimal robust optimization uncertainty settings for clinical head and neck cancer (HNC) patients undergoing 3D image-guided pencil beam scanning (PBS) proton therapy. MethodsWe analyzed ten consecutive HNC patients treated with 70 and 54.25 GyRBE to the primary and prophylactic clinical target volumes (CTV) respectively using intensity-modulated proton therapy (IMPT). Clinical plans were generated using robust optimization with 5 mm/3% setup/range uncertainties (RayStation v6.1). Additional plans were created for 4, 3, 2 and 1 mm setup and 3% range uncertainty and for 3 mm setup and 3%, 2% and 1% range uncertainty.Systematic and random error distributions were determined for setup and range uncertainties based on our quality assurance program. From these, 25 treatment scenarios were sampled for each plan, each consisting of a systematic setup and range error and daily random setup errors. Fraction doses were calculated on the weekly verification CT closest to the date of treatment as this was considered representative of the daily patient anatomy. ResultsPlans with a 2 mm/3% setup/range uncertainty setting adequately covered the primary and prophylactic CTV (V95 ≥ 99% in 98.8% and 90.8% of the treatment scenarios respectively). The average organ-at-risk dose decreased with 1.1 GyRBE/mm setup uncertainty reduction and 0.5 GyRBE/1% range uncertainty reduction. Normal tissue complication probabilities decreased by 2.0%/mm setup uncertainty reduction and by 0.9%/1% range uncertainty reduction. ConclusionThe results of this study indicate that margin reduction below 3 mm/3% is possible but requires a larger cohort to substantiate clinical introduction.

Sequential and Iterative Auto-Segmentation of High-Risk Clinical Target Volume for Radiotherapy of Nasopharyngeal Carcinoma in Planning CT Images.

Background: Accurate segmentation of tumor targets is critical for maximizing tumor control and minimizing normal tissue toxicity. We proposed a sequential and iterative U-Net (SI-Net) deep learning method to auto-segment the high-risk primary tumor clinical target volume (CTVp1) for treatment planning of nasopharyngeal carcinoma (NPC) radiotherapy.Methods: The SI-Net is a variant of the U-Net architecture. The input of SI-Net includes one CT image, the CTVp1 contour on this image, and the next CT image. The output is the predicted CTVp1 contour on the next CT image. We designed the SI-Net, using the left side to learn the volumetric features and the right to localize the contour on the next image. Two prediction directions, one from inferior to superior (forward direction) and the other from superior to inferior (backward direction), were tested. The performance was compared between the SI-Net and the U-Net using Dice similarity coefficient (DSC), Jaccard index (JI), average surface distance (ASD), and Hausdorff distance (HD) metrics.Results: The DSC and JI values from the forward direction SI-Net model were 5 and 6% higher than those from the U-Net model (0.84 ± 0.04 vs. 0.80 ± 0.05 and 0.74 ± 0.05 vs. 0.69 ± 0.05, p < 0.001). The smaller ASD and HD values also indicated a better performance (2.8 ± 1.0 vs. 3.3 ± 1.0 mm and 8.7 ± 2.5 vs. 9.7 ± 2.7 mm, p < 0.01) for the SI-Net model. For the backward direction SI-Net model, the DSC and JI values were still better than those from the U-Net model (p < 0.01), although there were no significant differences in ASD and HD.Conclusions: The SI-Net model preserved the continuity between adjacent images and thus improved the segmentation accuracy compared with the conventional U-Net model. This model has potential of improving the efficiency and consistence of CTVp1 contouring for NPC patients.

A Prospective 10-Year Observational Study of Reduction of Radiation Therapy Clinical Target Volume and Dose in Early-Stage Nasopharyngeal Carcinoma

Current guideline recommends a uniform method of delineation of subclinical disease within the primary clinical target volume (CTVp) for all stages of nasopharyngeal carcinoma (NPC). We performed a prospective observational study to investigate the outcomes with a reduced CTVp and radiation dose for early-stage NPC. Patients with newly diagnosed, biopsy-proven World Health Organization type II-III and American Joint Committee on Cancer/Union for International Cancer Control sixth edition stage T1-2N0-1 disease were enrolled. All patients were treated with intensity modulated radiation therapy alone. We categorized CTVp into CTVp1 (high risk) and CTVp2 (low risk). CTVp1 comprised of gross tumor (on magnetic resonance imaging or contrast-enhanced computed tomography) plus a 5-mm margin (3-mm posteriorly) and was prescribed to 60 Gy in 30 fractions (fr). CTVp2 was generated from CTVp1 plus a 5-mm margin (3 mm posteriorly), excluding the maxillary and cavernous sinuses, and was prescribed to 54 Gy in 30 fr. The prescribed doses to the primary and nodal gross tumor volume (GTVp and GTVn) were 68 Gy in 30 fr and 60 to 66 Gy in 30 fr, respectively. Primary endpoint was local recurrence-free survival. This study was registered in ClinicalTrials.gov, number NCT03839602. From May 2001 to August 2006, 103 patients were recruited and completed IMRT. With a median follow-up of 15.2 years (range, 2.1-18.1 years), only 1 patient had local failure. Ten-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, and overall survival were 90.3%, 88.3%, 90.3%, and 91.2%, respectively. Among late IMRT-related adverse events, we recorded 2 patients with G1 cranial nerve injury, 3 patients with G3 hearing loss, and 3 patients with G3 subcutaneous fibrosis. No patients had temporal lobe necrosis, brain stem injury, or trismus. Decreased CTV margins and radiation doses can achieve long-term tumor control with mild late toxicities for patients with early-stage NPC.

Prospective evaluation of definitive chemoradiotherapy with volumetric modulated arc therapy in patients with muscle invasive carcinoma of urinary bladder.

IntroductionConcurrent chemoradiotherapy (CTRT) remains one of the treatment options in patients with muscle invasive bladder cancer (MIBC) unwilling/unsuitable for radical surgery. We evaluated the role of volumetric modulated arc therapy (VMAT) in MIBC patients treated with definitive CTRT.Material and methods25 patients of histologically proven transitional cell MIBC (T2–T4a, N0, M0) unwilling/unsuitable for radical surgery (after maximal transurethral resection of bladder tumour) were recruited in this prospective study. Primary clinical target volume (CTV) consisted of the gross tumour and whole bladder. Primary planning target volume (PTV) and nodal PTV were prescribed 60 Gy and 54 Gy (both in 30 fractions). Concurrent chemotherapy was cisplatin (40 mg/m2) weekly. Acute toxicities were assessed as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Survival estimates were done from the date of registration using the Kaplan-Meier method.ResultsMedian age was 70 years (37–80 years). Median overall treatment time was 45 days (44–51). Median number of chemotherapy cycles was 5 (range 3–6). 5 (20%) and 4 (16%) patients respectively suffered from acute grade ≥ 2 gastrointestinal and grade ≥ 2 genitourinary toxicities during treatment. One patient each had grade 3 anaemia and neutropenia. At a median follow-up of 34 months (10–45 months), 3-year progression-free survival and overall survival were 65.6% and 81.2% respectively. 3-year distant metastasis-free survival was 90.5%. Bladder preservation rate at 3 years was 68%.ConclusionsDefinitive CTRT with VMAT is well tolerated in patients with MIBC unsuitable for surgery and yields decent survival and bladder preservation outcome.

Robust maximization of tumor control probability for radicality constrained radiotherapy dose painting by numbers of head and neck cancer.

Background and purposeRadiotherapy with dose painting by numbers (DPBN) needs another approach than conventional margins to ensure a geometrically robust dose coverage for the tumor. This study presents a method to optimize DPBN plans that as opposed to achieve a robust dose distribution instead robustly maximize the tumor control probability (TCP) for patients diagnosed with head and neck cancer.Material and methodsVolumetric-modulated arc therapy (VMAT) plans were optimized with a robust TCP maximizing objective for different dose constraints to the primary clinical target volume (CTVT) for a set of 20 patients. These plans were optimized with minimax optimization together with dose-responses driven by standardized uptake values (SUV) from 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET). The robustness in TCP was evaluated through sampling treatment scenarios with isocenter displacements.ResultsThe average increase in TCP with DPBN compared to a homogeneous dose treatment ranged between 3 and 20 percentage points (p.p.) which depended on the different dose constraints for the CTVT. The median deviation in TCP increase was below 1p.p. for all sampled treatment scenarios versus the nominal plans. The standard deviation of SUV multiplied by the CTVT volume were found to correlate with the TCP gain with R2 ≥ 0.9.ConclusionsMinimax optimization of DPBN plans yield, based on the presented TCP modelling, a robust increase of the TCP compared to homogeneous dose treatments for head and neck cancers. The greatest TCP gains were found for patients with large and SUV heterogeneous tumors, which may give guidance for patient selection in prospective trials.

Prospective Evaluation of Definitive Chemoradiotherapy with Volumetric Modulated Arc Therapy (VMAT) in Patients of Muscle Invasive Carcinoma of Urinary Bladder Unsuitable for Radical Surgery

Definitive Concurrent chemo-radiotherapy (CTRT) remains one of the treatment options in patients of muscle invasive bladder cancer (MIBC) deemed unsuitable for radical surgery. Radiotherapy (RT) with conventional techniques are associated with grade 3 gastrointestinal (GI) toxicities of 20-30%. We sought to evaluate the role of volumetric modulated arc therapy (VMAT) in patients of MIBC deemed unsuitable for radical surgery and treated with definitive CTRT. 20 patients of histologically proven transitional cell MIBC (T2 -T4a, N0-2, M0) unsuitable/unwilling for radical surgery were recruited in this prospective, interventional, single arm study (Jan 2016 to Jan 2018). All patients underwent maximal transurethral resection of bladder tumor. Primary clinical target volume (CTV) consisted of gross tumor and whole of bladder (prostate, prostatic urethra, proximal urethra included in selected cases). Nodal CTV included external iliac, internal iliac, obturator, sacral group of lymph nodes and gross nodes with 5-10 mm margins. Primary planning target volume (PTV) was generated with 1 cm expansion to internal target volume (ITV) and nodal PTV was generated by 7 mm margin to nodal CTV. Primary PTV and nodal PTV were prescribed a dose of 60 Gray and 54 Gray (both in 30 fractions) using VMAT technique. Concurrent chemotherapy was cisplatin (40 mg/m2) weekly. Constraints used for small bowel was V45<195 cc; Femoral heads Dmax <45 Gray and rectum V50<50%. Acute toxicities were assessed as per CTCAE version 4.0. Loco-regional control rate (LCR) and overall survival (OS) was defined from the date of registration till loco-regional failure or death from any cause respectively. Kaplan Meier method was used for analysis. Patient characteristics are summarized in table 1. All patients completed treatment without interruption. Median overall treatment time was 46 days (41-48). Median concurrent chemotherapy cycles were 5 (range 1-6). 7 (35%) and 3 (15%) patients respectively suffered from acute grade 2 GI and grade 2 genitourinary (GU) toxicities during treatment. Grade 2 leucopenia, anemia and thrombocytopenia was seen in 8(40%), 6(30%) and 2(10%) patients respectively. No patient incurred grade 3 or higher GI/GU/hematological toxicities. Median follow up was 34 months (12-40 months). At the time of last follow up, 2 patients (10%) developed distant metastasis alone and 3 patients (15%) developed loco-regional failure. 3-year LRC and OS was respectively 60.6% and 83.6% respectively. Definitive chemoradiotherapy with VMAT technique is well tolerated in patients of MIBC unsuitable for radical surgery and is associated with descent survival outcome.Abstract 2578; Table 1Patient characteristicsMedian age (range) years68 (37-80)Male: Female19:1Stage (number of patients) T2: T3:T4 N0: N2 II: III: IV12 (60%):4(20%):4(20%) 16 (80%):4(20%) 12 (60%):4(20%):4(20%)Grade High: Low18 (90%): 2(10%)Median KPS90 (80-90) Open table in a new tab