ROAR-A: re-optimization based Online Adaptive Radiotherapy of anal cancer, a prospective phase II trial protocol.

BACKGROUND: Chemo-radiotherapy with curative intent for anal cancer has high complete remission rates, but acute treatment-related gastrointestinal (GI) toxicity is significant. Toxicity occurs due to irradiation of surrounding normal tissue. Current radiotherapy requires the addition of large planning margins to the radiation field to ensure target coverage regardless of the considerable organ motion in the pelvic region. This increases the irradiated volume and radiation dose to the surrounding normal tissue and thereby toxicity. Online adaptive radiotherapy uses artificial intelligence to adjust the treatment to the anatomy of the day. This allows for the reduction of planning margins, minimizing the irradiated volume and thereby radiation to the surrounding normal tissue.This study examines if cone beam computed tomography (CBCT)-guided oART with daily automated treatment re-planning can reduce acute gastrointestinal toxicity in patients with anal cancer. METHODS/DESIGN: The study is a prospective, single-arm, phase II trial conducted at Copenhagen University Hospital, Herlev and Gentofte, Denmark. 205 patients with local only or locally advanced anal cancer, referred for radiotherapy with or without chemotherapy with curative intent, are planned for inclusion. Toxicity and quality of life are reported with Common Terminology Criteria of Adverse Events and patient-reported outcome questionnaires, before, during, and after treatment. The primary endpoint is a reduction in the incidence of acute treatment-related grade ≥ 2 diarrhea from 36 to 25% after daily online adaptive radiotherapy compared to standard radiotherapy. Secondary endpoints include all acute and late toxicity, overall survival, and reduction in treatment interruptions. RESULTS: Accrual began in January 2022 and is expected to finish in January 2026. Primary endpoint results are expected to be available in April 2026. DISCUSSION: This is the first study utilizing online adaptive radiotherapy to treat anal cancer. We hope to determine whether there is a clinical benefit for the patients, with significant reductions in acute GI toxicity without compromising treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05438836. Danish Ethical Committee: H-21028093.

Interim analysis of patient-reported outcome compliance and dosimetry in a phase 3 randomized clinical trial of oesophagus-sparing spinal radiotherapy.

BACKGROUND: The randomized clinical trial ESO-SPARE investigates if oesophagus-sparing radiotherapy (RT) can reduce dysphagia in patients with metastatic spinal cord compression (MSCC). Patient-reported outcome (PRO) is the only follow-up measure. Due to the fragile patient population, low respondent compliance was anticipated. We performed a planned interim analysis of dosimetry and respondent compliance, to ensure that the protocol requirements were met. METHODS: Patients >18 years referred for cervical/thoracic MSCC radiotherapy in 1-10 fractions were included from two centres. Patients were randomized (1:1) to standard RT or oesophagus-sparing RT, where predefined oesophageal dose constraints were prioritized over target coverage. Patients completed a trial diary with daily reports of dysphagia for 5 weeks (PRO-CTC-AE) and weekly quality of life reports for 9 weeks (QLQ-C30, EQ-5D-5L). According to power calculation, 124 patients are needed for primary endpoint analysis. The sample size was inflated to 200 patients to account for the fragile patient population. The co-primary endpoints, peak patient-reported dysphagia, and preserved ability to walk (EQ-5D-5L), are analysed at 5 and 9 weeks, respectively. The interim analysis was conducted 90 days after the inclusion of patient no 100. Respondent compliance was assessed at 5 and 9 weeks. In all RT plans, oesophagus and target doses were evaluated regarding adherence to protocol constraints. RESULTS: From May 2021 to November 2022, 100 patients were included. Fifty-two were randomized to oesophagus-sparing RT. In 23% of these plans, oesophagus constraints were violated. Overall, the dose to both target and oesophagus was significantly lower in the oesophagus-sparing plans. Only 51% and 41% of the patients were evaluable for co-primary endpoint analysis at five and nine weeks, respectively. Mortality and hospitalization rates were significantly larger in patients who completed <4 days PRO questionnaires. CONCLUSION: Compliance was lower than anticipated and interventions to maintain study power are needed.

Consistency in contouring of organs at risk by artificial intelligence vs oncologists in head and neck cancer patients.

BACKGROUND: In the Danish Head and Neck Cancer Group (DAHANCA) 35 trial, patients are selected for proton treatment based on simulated reductions of Normal Tissue Complication Probability (NTCP) for proton compared to photon treatment at the referring departments. After inclusion in the trial, immobilization, scanning, contouring and planning are repeated at the national proton centre. The new contours could result in reduced expected NTCP gain of the proton plan, resulting in a loss of validity in the selection process. The present study evaluates if contour consistency can be improved by having access to AI (Artificial Intelligence) based contours. MATERIALS AND METHODS: The 63 patients in the DAHANCA 35 pilot trial had a CT from the local DAHANCA centre and one from the proton centre. A nationally validated convolutional neural network, based on nnU-Net, was used to contour OARs on both scans for each patient. Using deformable image registration, local AI and oncologist contours were transferred to the proton centre scans for comparison. Consistency was calculated with the Dice Similarity Coefficient (DSC) and Mean Surface Distance (MSD), comparing contours from AI to AI and oncologist to oncologist, respectively. Two NTCP models were applied to calculate NTCP for xerostomia and dysphagia. RESULTS: The AI contours showed significantly better consistency than the contours by oncologists. The median and interquartile range of DSC was 0.85 [0.78 - 0.90] and 0.68 [0.51 - 0.80] for AI and oncologist contours, respectively. The median and interquartile range of MSD was 0.9 mm [0.7 - 1.1] mm and 1.9 mm [1.5 - 2.6] mm for AI and oncologist contours, respectively. There was no significant difference in ΔNTCP. CONCLUSIONS: The study showed that OAR contours made by the AI algorithm were more consistent than those made by oncologists. No significant impact on the ΔNTCP calculations could be discerned.

Single-isocenter stereotactic non-coplanar arc treatment of 200 patients with brain metastases: multileaf collimator size and setup uncertainties.

PURPOSE: The purpose of this study was to evaluate our 2 years' experience with single-isocenter, non-coplanar, volumetric modulated arc therapy (VMAT) for brain metastasis (BM) stereotactic radiosurgery (SRS). METHODS: A total of 202 patients treated with the VMAT SRS solution were analyzed retrospectively. Plan quality was assessed for 5 mm (120) and 2.5 mm (high-definition, HD) central leaf width multileaf collimators (MLCs). For BMs at varying distances from the plan isocenter, the geometric offset from the ideal position for two image-guided radiotherapy workflows was calculated. In the workflow with ExacTrac (BrainLAB, München, Germany; W­ET), patient positioning errors were corrected at each couch rotation. In the workflow without ExacTrac (W-noET), only the initial patient setup correction was considered. The dose variation due to rotational errors was simulated for multiple-BM plans with the HD-MLC. RESULTS: Plan conformity and quality assurance were equivalent for plans delivered with the two MLCs while the HD-MLC plans provided better healthy brain tissue (BmP) sparing. 95% of the BMs had residual intrafractional setup errors ≤ 2 mm for W­ET and 68% for W­noET. For small BM (≤1 cc) situated >3 cm from the plan isocenter, the dose received by 95% of the BM decreased in median (interquartile range) by 6.3% (2.8-8.8%) for a 1-degree rotational error. CONCLUSION: This study indicates that the HD-MLC is advantageous compared to the 120-MLC for sparing healthy brain tissue. When a 2-mm margin is applied, W­noET is sufficient to ensure coverage of BM situated ≤ 3 cm of the plan isocenter, while for BM further away, W­ET is recommended.

Adaptation requirements due to anatomical changes in free-breathing and deep-inspiration breath-hold for standard and dose-escalated radiotherapy of lung cancer patients.

BACKGROUND: Radiotherapy of lung cancer patients is subject to uncertainties related to heterogeneities, anatomical changes and breathing motion. Use of deep-inspiration breath-hold (DIBH) can reduce the treated volume, potentially enabling dose-escalated (DE) treatments. This study was designed to investigate the need for adaptation due to anatomical changes, for both standard (ST) and DE plans in free-breathing (FB) and DIBH. MATERIAL AND METHODS: The effect of tumor shrinkage (TS), pleural effusion (PE) and atelectasis was investigated for patients and for a CIRS thorax phantom. Sixteen patients were computed tomography (CT) imaged both in FB and DIBH. Anatomical changes were simulated by CT information editing and re-calculations, of both ST and DE plans, in the treatment planning system. PE was systematically simulated by adding fluid in the dorsal region of the lung and TS by reduction of the tumor volume. RESULTS: Phantom simulations resulted in maximum deviations in mean dose to the GTV-T (GTV-T) of -1% for 3 cm PE and centrally located tumor, and + 3% for TS from 5 cm to 1 cm diameter for an anterior tumor location. For the majority of the patients, simulated PE resulted in a decreasing GTV-T with increasing amount of fluid and increasing GTV-T for decreasing tumor volume. Maximum change in GTV-T of -3% (3 cm PE in FB for both ST and DE plans) and + 10% (2 cm TS in FB for DE plan) was observed. Large atelectasis reduction increased the GTV-T with 2% for FB and had no effect for DIBH. CONCLUSION: Phantom simulations provided potential adaptation action levels for PE and TS. For the more complex patient geometry, individual assessment of the dosimetric impact is recommended for both ST and DE plans in DIBH as well as in FB. However, DIBH was found to be superior over FB for DE plans, regarding robustness of GTV-T to TS.

Evaluation of decentralised model-based selection of head and neck cancer patients for a proton treatment study. DAHANCA 35.

INTRODUCTION: Proton treatment can potentially spare patients with H&N cancer for substantial treatment-related toxicities. The current study investigated the reproducibility of a decentralised model-based selection of patients for a proton treatment study when the selection plans were compared to the clinical treatment plans performed at the proton centre. METHODS: Sixty-three patients were selected for proton treatment in the six Danish Head and Neck Cancer (DAHANCA) centres. The patients were selected based on normal tissue complication probability (NTCP) estimated from local photon and proton treatment plans, which showed a ΔNTCP greater than 5%-point for either grade 2 + dysphagia or grade 2 + xerostomia at six months. The selection plans were compared to the clinical treatment plans performed at the proton centre. RESULTS: Of the 63 patients, 49 and 25 were selected based on an estimated benefit in risk of dysphagia and xerostomia, respectively. Eleven patients had a potential gain in both toxicities. The mean ΔNTCP changed from the local selection plan comparison to the clinical comparison from 6.9 to 5.3 %-points (p = 0.01) and 7.3 to 4.9 %-points (p = 0.03) for dysphagia and xerostomia, respectively. Volume differences in both CTV and OAR could add to the loss in ΔNTCP. 61 of the 63 clinical plans had a positive ΔNTCP, and 38 had a ΔNTCP of 5%-points for at least one of the two endpoints. CONCLUSION: A local treatment plan comparison can be used to select candidates for proton treatment. The local comparative proton plan overestimates the potential benefit of the clinical proton plan. Continuous quality assurance of the delineation procedures and planning is crucial in the subsequent randomised clinical trial setting.

Online adaptive radiotherapy of anal cancer: Normal tissue sparing, target propagation methods, and first clinical experience.

BACKGROUND AND PURPOSE: Online adaptive radiotherapy (oART) potentially spares OARs as PTV margins are reduced. This study evaluates dosimetric benefits, compared to standard non-adaptive radiotherapy (non-ART), target propagation methods, and first clinical treatments of CBCT-guided oART of anal cancer. MATERIALS AND METHODS: Treatment plans with standard non-ART and reduced oART PTV margins were retrospectively generated for 23 consecutive patients with anal cancer. For five patients randomly selected among the 23 patients, weekly CBCT-guided oART sessions were simulated, where the targets were either deformed or rigidly propagated. Preferred target propagation method and dose to OARs were evaluated. Ten consecutive patients with anal cancer were treated with CBCT-guided oART. Target propagation methods and oART procedure time were evaluated. RESULTS: For the retrospective treatment plans, oART resulted in median reductions in bowel bag V45Gy of 11.4 % and bladder V35Gy of 16.1%. Corresponding values for the simulated sessions were 7.5% and 27.1%. In the simulated sessions, 35% of all targets were deformed while 65% were rigidly propagated. Manual editing and rigid propagation were necessary to obtain acceptable target coverage. In the clinical treatments, the primary and some elective targets were rigidly propagated, while other targets were deformed. The median oART procedure time, measured from CBCT acquisition to completion of plan review and QA, was 23 min. CONCLUSIONS: Simulated oART reduced the dose to OARs, indicating potential reduction in toxicity. Rigid propagation of targets was necessary to reduce the need for manual edit. Clinical treatments demonstrated that oART of anal cancer is feasible but time-consuming.

Online adaptive radiotherapy of urinary bladder cancer with full re-optimization to the anatomy of the day: Initial experience and dosimetric benefits.

BACKGROUND AND PURPOSE: Online adaptive radiotherapy (oART) potentially reduces the dose to organs at risk (OARs) as the planning target volume (PTV) margins are reduced compared to a non-adaptive approach (non-ART). This study evaluates the feasibility and dosimetric impact of cone-beam computed tomography (CBCT)-guided oART of urinary bladder cancer for the first patients treated, using patient-specific margins. MATERIALS AND METHODS: Sixteen consecutive patients with muscle-invasive bladder cancer received two or more (median = 23) fractions as oART, and remaining fractions as non-ART. The non-ART fractions were delivered with standard population-based margins, while reduced patient-specific margins based on intra-fractional variations extracted from 2-4 fractions were applied to the primary PTV (PTV-T) during the oART fractions. Target volume and coverage, and dose to OARs were compared between non-ART and oART plans, and the oART procedure time was recorded. RESULTS: In total, 297/512 fractions were delivered as oART with full re-optimization to the anatomy of the day. The median (interquartile range, IQR) oART procedure time, measured from the end of CBCT generation to completion of plan review, and quality assurance was 13.9 (11.9;16.6) min. The median (IQR) volume reduction in PTV-T volume was 33.9 (24.2;45.0)%, comparing oART and non-ART plans, resulting in median (IQR) reductions in bowel bag V45Gy of 18.8 (12.7;27.9)% and rectum V50Gy of 70.7 (35.9;94.8)%. By re-optimizing the plan to the daily anatomy, full target coverage was achieved at all oART fractions. CONCLUSIONS: oART resulted in large reductions in treatment volumes and doses to OARs, compared to non-ART, while ensuring target coverage. This indicates potential reductions in gastrointestinal toxicity.

Evaluation of an automated template-based treatment planning system for radiotherapy of anal, rectal and prostate cancer.

Background and purpose: The Ethos system has enabled online adaptive radiotherapy (oART) by implementing an automated treatment planning system (aTPS) for both intensity-modulated radiotherapy (IMRT) and volumetric modulated arc radiotherapy (VMAT) plan creation. The purpose of this study is to evaluate the quality of aTPS plans in the pelvic region. Material and Methods: Sixty patients with anal (n = 20), rectal (n = 20) or prostate (n = 20) cancer were retrospectively re-planned with the aTPS. Three IMRT (7-, 9- and 12-field) and two VMAT (2 and 3 arc) automatically generated plans (APs) were created per patient. The duration of the automated plan generation was registered. The best IMRT-AP and VMAT-AP for each patient were selected based on target coverage and dose to organs at risk (OARs). The AP quality was analyzed and compared to corresponding clinically accepted and manually generated VMAT plans (MPs) using several clinically relevant dose metrics. Calculation-based pre-treatment plan quality assurance (QA) was performed for all plans. Results: The median total duration to generate the five APs with the aTPS was 55 min, 39 min and 35 min for anal, prostate and rectal plans, respectively. The target coverage and the OAR sparing were equivalent for IMRT-APs and VMAT-MPs, while VMAT-Aps.demonstrated lower target dose homogeneity and higher dose to some OARs. Both conformity and homogeneity index were equivalent (rectal) or better (anal and prostate) for IMRT-APs compared to VMAT-MPs. All plans passed the patient-specific QA tolerance limit. Conclusions: The aTPS generates plans comparable to MPs within a short time-frame which is highly relevant for oART treatments.

Clinical implementation of artificial intelligence-driven cone-beam computed tomography-guided online adaptive radiotherapy in the pelvic region.

BACKGROUND AND PURPOSE: Studies have demonstrated the potential of online adaptive radiotherapy (oART). However, routine use has been limited due to resource demanding solutions. This study reports on experiences with oART in the pelvic region using a novel cone-beam computed tomography (CBCT)-based, artificial intelligence (AI)-driven solution. MATERIAL AND METHODS: Automated pre-treatment planning for thirty-nine pelvic cases (bladder, rectum, anal, and prostate), and one hundred oART simulations were conducted in a pre-clinical release of Ethos (Varian Medical Systems, Palo Alto, CA). Plan quality, AI-segmentation accuracy, oART feasibility and an integrated calculation-based quality assurance solution were evaluated. Experiences from the first five clinical oART patients (three bladder, one rectum and one sarcoma) are reported. RESULTS: Auto-generated pre-treatment plans demonstrated similar planning target volume (PTV) coverage and organs at risk doses, compared to institution reference. More than 75% of AI-segmentations during simulated oART required none or minor editing and the adapted plan was superior in 88% of cases. Limitations in AI-segmentation correlated to cases where AI model training was lacking. The five first treated patients complied well with the median adaptive procedure duration of 17.6 min (from CBCT acceptance to treatment delivery start). The treated bladder patients demonstrated a 42% median primary PTV reduction, indicating a 24%-30% reduction in V45Gy to the bowel cavity, compared to non-ART. CONCLUSIONS: A novel commercial oART solution was demonstrated feasible for various pelvic sites. Clinically acceptable AI-segmentation and auto-planning enabled adaptation within reasonable timeslots. Possibilities for reduced PTVs observed for bladder cancer indicated potential for toxicity reductions.

Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.

BACKGROUND AND PURPOSE: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. MATERIAL AND METHODS: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. RESULTS: The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. CONCLUSIONS: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

The advantage of deep-inspiration breath-hold and cone-beam CT based soft-tissue registration for locally advanced lung cancer radiotherapy.

BACKGROUND AND PURPOSE: Three cone-beam computed tomography (CBCT) registration strategies combined with deep-inspiration breath-hold (DIBH) and free-breathing (FB) were explored, in terms of obtaining the smallest planning target volume (PTV). MATERIAL AND METHODS: CBCT images were acquired pre- and post-treatment in FB and DIBH, for 17 locally advanced lung cancer patients. Bony registration on the spine, and soft-tissue registrations on the primary gross tumor volume (GTV-T) and GTV-Total, including malignant lymph nodes (GTV-N), were retrospectively analyzed. Setup-margins and resulting PTVs were calculated. RESULTS: For the spine, the smallest residual misalignments were observed in FB, independently of registration method. For GTV-T and GTV-N, soft-tissue registrations were superior to bony registration, independently of FB or DIBH. Compared to FB, PTV-Totals were during DIBH reduced by 13% and 8% for the soft-tissue and bony registrations, respectively. If intra-fractional motion was included, the corresponding gain of DIBH was reduced to 9% and 7%, respectively. Superiority of DIBH was mainly due to larger clinical target volumes in FB. CONCLUSIONS: Despite larger setup uncertainties compared to FB, DIBH resulted in smaller PTV-Totals for all registration methods. Soft-tissue registrations were superior to bony registration, independently of FB and DIBH. During DIBH, undesirable arching of the back was identified. Daily CBCT pre-treatment target verification is advised.

Monte Carlo calculations support organ sparing in Deep-Inspiration Breath-Hold intensity-modulated radiotherapy for locally advanced lung cancer.

BACKGROUND AND PURPOSE: Studies indicate that Deep-Inspiration Breath-Hold (DIBH) is advantageous over Free-Breathing (FB) for locally advanced lung cancer radiotherapy. However, these studies were based on simplified dose calculation algorithms, potentially critical due to the heterogeneous nature of the lung region. Using detailed Monte-Carlo (MC) calculations, a comparative study of DIBH vs. FB was therefore designed. MATERIAL AND METHODS: Eighteen locally advanced lung cancer patients underwent FB and DIBH CT imaging and treatment planning with the Anisotropic-Analytical-Algorithm (AAA) for intensity-modulated-radiotherapy or volumetric-modulated-arc-therapy using 66Gy in 33 fractions. All plans were re-calculated with MC. RESULTS: Relative to FB, the total lung volume increased 86.8% in DIBH, while the gross tumor volume decreased 14.8%. MC revealed equally under- and over-dosage of the target for FB and DIBH, compared to AAA. For the Organs-At-Risk (OARs), DIBH reduced the mean heart dose by 25.5% (AAA) vs. 12.6% (MC), the total lung V5Gy/V20Gy by 9.0/20.0% (AAA) vs. 11.6/19.9% (MC). CONCLUSIONS: MC calculations revealed (i) that DIBH compared with FB can significantly reduce the dose to the OARs even if the treatment planning is carried out with AAA, and (ii) inferior target dose coverage compared to AAA, irrespectively of FB and DIBH. The dose deviations were similar for FB and DIBH. The observed inferior target dose coverage relates therefore to the treatment planning algorithm rather than breathing technique.