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The field of radiation oncology is rapidly advancing through technological and biomedical innovation backed by robust research evidence. In addition, cancer professionals are notoriously time-poor, meaning there is a need for high quality, accessible and tailored oncological education programs. Digital learning (DL) is well-placed to cater to these needs, as it provides teaching options that can be delivered flexibly and on-demand from anywhere in the world. The evidence for usage of these techniques in medical education has expanded rapidly in recent years. However, there remains many reservations in the oncological community to adopting and developing DL, largely due to a poor familiarity with the pedagogical evidence base. This article will review the application of the screen-based DL tools that are at educators' disposal. It will summarize best-practice in developing tailored, made-for-screen videos, gamification, and infographics. It also reviews data behind the following practical tips of 1) strategically combining text with graphics to decrease cognitive load, 2) engaging users through use of interactive elements in digital content, and 3) maximizing impact through thoughtful organization of animations/images. Overall, the digital space evolving is well placed to cater to the evolving educational needs of oncology learners. This review and its practical tips aim to inspire further development in this arena, production of high-yield educational products, use of engaging delivery methods and programs that are tailored to individual learning needs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Abstract: Volumetric imaging and planning for 3-dimensional (3D) conformal radiotherapy and intensity-modulated radiotherapy (IMRT) have highlighted the need to the oncology community to better understand the geometric uncertainties inherent in the radiotherapy delivery process, including setup error (interfraction) as well as organ motion during treatment (intrafraction). This has ushered in the development of emerging technologies and clinical processes, collectively referred to as image-guided radiotherapy (IGRT). The goal of IGRT is to provide the tools needed to manage both inter- and intrafraction motion to improve the accuracy of treatment delivery. Like IMRT, IGRT is a process involving all steps in the radiotherapy treatment process, including patient immobilization, computed tomogaphy (CT) simulation, treatment planning, plan verification, patient setup verification and correction, delivery, and quality assurance. The technology and capability of the Dynamic Targeting™ IGRT system developed by Varian Medical Systems is presented. The core of this system is a Clinac® or Trilogy™ accelerator equipped with a gantry-mounted imaging system known as the On-Board Imager™ (OBI). This includes a kilovoltage (kV) x-ray source, an amorphous silicon kV digital image detector, and 2 robotic arms that independently position the kV source and imager orthogonal to the treatment beam. A similar robotic arm positions the PortalVision™ megavoltage (MV) portal digital image detector, allowing both to be used in concert. The system is designed to support a variety of imaging modalities. The following applications and how they fit in the overall clinical process are described: kV and MV planar radiographic imaging for patient repositioning, kV volumetric cone beam CT imaging for patient repositioning, and kV planar fluoroscopic imaging for gating verification. Achieving image-guided motion management throughout the radiation oncology process requires not just a single product, but a suite of integrated products to manipulate all patient data, including images, efficiently and effectively. [Copyright &y& Elsevier]

Background: The watch and wait (W&W) strategy is proposed for patients with locally advanced rectal cancer (LARC) achieving clinical complete response (cCR) after neoadjuvant radiotherapy. cCR is only in partial concordance with pathological complete response (pCR) due to persisting viable tumour cells. The aim was to investigate circulating-free-deoxyribonucleic-acid (cfDNA) as a biomarker for prediction of pCR., Materials and Methods: Patients treated with neoadjuvant radiotherapy for LARC, were included in a prospective biomarker study in Aarhus, Denmark from 2017 to 2020. Plasma cfDNA levels were analysed by a direct fluorescent assay (DFA). Surgical specimens were reviewed by pathologists to categorize response to cytotoxic therapy., Results: In total, 76 patients were included with plasma available at baseline (n = 70), mid therapy (n = 50), and end of therapy (n = 54). Higher cfDNA levels were observed in LARC patients compared with healthy subjects (p < 0.01). By ROC analysis (AUC: 0.87 (95% CI, 0.81-0.92)) the optimal cut-off was 0.71 ng/µL for differentiation between healthy subjects and LARC patients. Thirteen patients obtained pCR with a median cfDNA level of 0.57 ng/µL at end of therapy. Patients with cfDNA levels at end of therapy below the cut-off (p < 0.02) and 'cfDNA responders' with descending levels greater than the 75th percentile during therapy had a significantly higher chance of pCR (p < 0.01)., Conclusion: This hypothesis generating study indicates that low cfDNA levels at end of treatment or ´cfDNA responderś might be associated with pCR. Quantification of cfDNA by the rapid and feasible DFA analysis could potentially facilitate personalized follow-up as a complementary tool to identify candidates for a W&W strategy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Purpose: Recent advances in the treatment algorithm of locally advanced rectal cancer (LARC) have significantly improved complete response (CR) rates and disease-free survival (DFS), but therapy resistance, with its substantial impact on outcomes and survival, remains a major challenge. Our group has recently unraveled a critical role of interleukin-1α (IL-1α) signaling in activating inflammatory cancer-associated fibroblasts (iCAFs) and mediating radiation-induced senescence, extracellular matrix (ECM) accumulation, and ultimately therapy resistance. We here summarize the recently initiated ACO/ARO/AIO-21 phase I trial, testing the IL-1 receptor antagonist (IL-1 RA) anakinra in combination with fluoropyrimidine-based chemoradiotherapy (CRT) for advanced rectal cancer., Methods/design: The ACO/ARO/AIO-21 is an investigator-driven, prospective, open-labeled phase I drug-repurposing trial assessing the maximum tolerated dose (MTD) of capecitabine administered concurrently to standard preoperative radiotherapy (45 Gy in 25 fractions followed by 9 Gy boost in 5 fractions) in combination with fixed doses of the IL1-RA anakinra (100 mg, days -10 to 30). Capecitabine will be administered using a 3 + 3 dose-escalation design (500 mg/m 2 bid; 650 mg/m 2 bid; 825 mg/m 2 bid, respectively) from day 1 to day 30. Response assessment including digital rectal examination (DRE), endoscopy and pelvic magnetic resonance imaging (MRI) is scheduled 10 weeks after completion of CRT. For patients achieving clinical complete response (cCR), primary non-operative management is provided. In case of non-cCR immediate total mesorectal excision (TME) will be performed. Primary endpoint of this phase I trial is the MTD of capecitabine., Discussion: Based on extensive preclinical research, the ACO/ARO/AIO-21 phase I trial will assess whether the IL-1RA anakinra can be safely combined with fluoropyrimidine-based CRT in rectal cancer. It will further explore the potential of IL-1 inhibition to overcome therapy resistance and improve response rates. A comprehensive translational research program will expand our understanding from a clinical perspective and may help translate the results into a randomized phase II trial., Competing Interests: The trial is sponsored by the LOEWE-Zentrum Frankfurt Cancer Institute (FCI) [III L 5 - 519/03/03.001 – (0015), PI: Emmanouil Fokas]. The authors have no further conflicts of interest to declare., (© 2022 The Author(s).)

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients., Methods and Materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later., Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors., Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background and Purpose: This systematic review aims to identify radiation dose-volume predictors of primary hypothyroidism after radiotherapy in patients with head and neck cancer (HNC)., Materials and Methods: We performed a systematic literature search of Medline, EMBASE and Web of Science from database inception to July 1, 2021 for articles that discuss radiation dose-volume predictors of post-radiation primary hypothyroidism in patients with HNC. Data on the incidence, clinical risk factors and radiation dose-volume parameters were extracted. A meta-analysis was performed using the random-effects model to estimate the pooled odds ratio (OR) of thyroid volume as a predictor of the risk of post-radiation hypothyroidism, adjusted for thyroid radiation dosimetry., Results: Our search identified 29 observational studies involving 4,530 patients. With median follow-up durations ranging from 1.0 to 5.3 years, the average crude incidence of post-radiation primary hypothyroidism was 41.4 % (range, 10 %-57 %). Multiple radiation dose-volume parameters were associated with post-radiation primary hypothyroidism, including the thyroid mean dose (Dmean), minimum dose, V25, V30, V35, V45, V50, V30-60, VS45 and VS60. Thyroid Dmean and V50 were the most frequently proposed dosimetric predictors. The pooled adjusted OR of thyroid volume on the risk of post-radiation primary hypothyroidism was 0.89 (95 % confidence interval, 0.85-0.93; p < 0.001) per 1 cc increment., Conclusion: Post-radiation primary hypothyroidism is a common late complication after radiotherapy for HNC. Minimizing inadvertent exposure of the thyroid gland to radiation is crucial to prevent this late complication. Radiation dose-volume constraints individualized for thyroid volume should be considered in HNC radiotherapy planning., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background and Purpose: Deep inspiration breath-hold is an established technique to reduce heart dose during breast cancer radiotherapy. However, modern breast cancer radiotherapy techniques with lymph node irradiation often require long beam-on times of up to 5 min. Therefore, the combination with deep inspiration breath-hold (DIBH) becomes challenging. A simple support technique for longer duration deep inspiration breath-hold (L-DIBH), feasible for daily use at the radiotherapy department, is required to maximize heart sparing., Materials and Methods: At our department, a new protocol for multiple L-DIBH of at least 2 min and 30 s was developed on 32 healthy volunteers and validated on 8 breast cancer patients during radiotherapy treatment, using a pragmatic process of iterative development, including all major stakeholders. Each participant performed 12 L-DIBHs, on 4 different days. Different methods of pre-oxygenation and voluntary hyperventilation were tested, and scored on L-DIBH duration, ease of use, and comfort., Results: Based on 384 L-DIBHs from 32 healthy volunteers, voluntary hyperventilation for 3 min whilst receiving high-flow nasal oxygen at 40 L/min was the most promising technique. During validation, the median L-DIBH duration in prone position of 8 breast cancer patients improved from 59 s without support to 3 min and 9 s using the technique (p < 0.001)., Conclusion: A new and simple L-DIBH protocol was developed feasible for daily use at the radiotherapy center., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: Locoregional recurrence remains a major cause of failure in head and neck squamous cell carcinoma (HNSCC). Human papilloma virus (HPV)-associated HNSCCs generally have a good prognosis but may recur even after standard photon radiotherapy (RT). Another incentive in observing patterns of recurrence is increased use of highly conformal techniques such as proton therapy. We therefore studied geographic distribution of recurrent tumors in relation to the high-risk treatment volume in a cohort of patients with HNSCC receiving combined modality therapy., Methods: Medical records of 508 patients diagnosed with HNSCC in 2010-2015 were reviewed. We identified a subgroup that had local and/or regional recurrence at hybrid positron emission tomography (PET)/computed tomography (CT) and/or magnetic resonance imaging (MRI). We adapted p16 as a surrogate marker for HPV-positivity and only patients with known p16 status were eligible for a detailed analysis where recurrent tumor was copied on the planning CT and the dose received by the recurrent tumor volume was determined using dose-volume histograms., Results: Twenty-five patients who had received either cisplatin (n = 23) or cetuximab-enhanced (n = 2) RT were identified. 31 locoregional recurrent tumors were detected among 18 p16 negative and 7 p16 positive patients. Of recurrent tumors 14 (45%) were classified as in-field, 5 (16%) as marginal miss, and 12 (39%) as true miss. p16 positive patients had 4 in-field, 2 marginal, and 1 true miss. By contrast, p16 negative patients had 10 in-field, 3 marginal, and 11 true miss recurrences., Conclusions: Both p16 positive and negative HNSCC recur in high-risk treatment volume despite the common view of high radiosensitivity of the former. Biomarkers predicting radioresistance should be characterized in p16 positive tumors before widely embarking on de-escalated CRT protocols. Another concern is how to decrease the number of true or marginal misses in p16 negative cases despite multimodality imaging-based target delineation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Aim: The purpose of this study was to review genitourinary (GU) and gastrointestinal (GI) toxicity associated with high-dose radiotherapy (RT) delivered with 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT) following radical prostatectomy (RP)., Background: RP is a therapeutic option for the management of prostate cancer (PrCa). When assessing postoperative RT techniques for PrCa, the published literature focuses on patients treated with 2-dimensional conventional methods without reflecting the implementation of 3D-CRT, IMRT, or VMAT., Materials and Methods: A total of 83 patients were included in this analysis; 30 patients received 3D-CRT, and 53 patients received IMRT/VMAT. Acute and late symptoms of the GU and lower GI tract were retrospectively graded according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer radiation toxicity grading systems. The relapse failure-free rate and overall survival were also evaluated., Results: The rate of acute GU toxicity was 9.4% vs. 13.3% for the IMRT/VMAT and 3D-CRT groups (p = 0.583). The 5-year actuarial rates of late GI toxicity for IMRT/VMAT and 3D-CRT treatments were 1.9% and 6.7%, respectively. The rate of late GU toxicity for the IMRT/VMAT and 3D-CRT treatment groups was 7.5% and 16.6%, respectively (p = 0.199). We found no association between acute or late toxicity and the RT technique in univariate and multivariate analyses., Conclusion: Postprostatectomy IMRT/VMAT and 3D-CRT achieved similar morbidity and cancer control outcomes. The clinical benefit of highly conformal techniques in this setting is unclear although formal analysis is needed., (© 2020 Greater Poland Cancer Centre. Published by Elsevier B.V. All rights reserved.)

Background: The vast majority of patients with head and neck squamous cell carcinoma (HNSCC) routinely undergo elective nodal irradiation (ENI) to both sides of the neck. Little is known about the extent to which bilateral ENI prevents regional failure (RF) and contralateral RF (cRF) in particular, while such knowledge is necessary to evaluate the results of more selective approaches like unilateral ENI. We investigated the rate and pattern of RF after bilateral ENI, the rate of cRF in the electively irradiated contralateral neck, and tried to identify risk factors for development of cRF., Materials and Methods: Retrospective cohort study of a consecutive series of 605 patients with T1-4N0-3 HNSCC treated between 2008 and 2017 with primary (chemo)radiation and bilateral ENI., Results: Median follow-up was 43 months (range 1.4-126). Three-year cumulative incidence of RF was 12.7%. Three-year cumulative incidences of ipsilateral RF (iRF) and cRF were 10.6% and 2.8%, respectively. All cRF occurred within the electively treated volume. Salvage treatment was possible in 65% and 59% of patients with iRF and cRF, respectively (p = 0.746). The 3-year overall survival rates after RF in patients with iRF and cRF were 27.4% and 41.2%, respectively (p = 0.713). Three-year cancer-specific survival rates were 31.6% and 48.1%, respectively (p = 0.634). In multivariate analysis, no significant predictive factors were identified for cRF after bilateral ENI., Conclusion: Contralateral regional failure is rare, but still occurs in 2.8% of patients treated with bilateral ENI. The possibilities for salvage treatment, the rates of overall survival and cancer-specific survival were comparable to patients with iRF.

Background and Purpose: Appropriate internal margins are essential to avoid a geographical miss in intensity-modulated radiation therapy (IMRT) for endometrial cancer (EC). This study evaluated interfraction target motion using rigid and non-rigid approximation strategies and calculated internal margins based on random and systematic errors using traditional rigid margin recipes. Dosimetric impact of target motion was also investigated., Materials and Methods: Cone beam CTs (CBCTs) were acquired days 1-4 and then weekly in 17 patients receiving adjuvant IMRT for EC; a total of 169 CBCTs were analysed. Interfraction motion for the clinical target volume vaginal vault and upper vagina (CTVv) was measured using bony landmarks and deformation vector field displacement (DVFD) within a 1 mm internal wall of CTVv. Patient and population systematic and random errors were estimated and margins calculated. Delivered dose to the CTVv and organs at risk was estimated., Results: There was a significant difference in target motion assessment using the different registration strategies (p < 0.05). DVFD up to 30 mm occurred in the anterior/posterior direction, which was not accounted for in PTV margins using rigid margin recipes. Underdosing of CTVv D95% occurred in three patients who had substantial reductions in rectal volume (RV) during treatment. RV relative to the planning CT was moderately correlated with anterior/posterior displacement (r = 0.6) and mean relative RV during treatment was strongly correlated with mean relative RV at CBCT acquired days 1-3 (r = 0.8)., Conclusion: Complex and extensive geometric changes occur to the CTVv, which are not accounted for in margin recipes using rigid approximation. Contemporary margin recipes and adaptive treatment planning based on non-rigid approximation are recommended., (© 2019 The Authors.)

Aim: To identify the most reproducible technique of patient positioning and immobilization during pelvic radiotherapy., Background: Radiotherapy plays an important role in the treatment of pelvic malignancies. Errors in positioning of patient are an integral component of treatment. The present study compares two methods of immobilization with no immobilization with an aim of identifying the most reproducible method., Materials and Methods: 65 consecutive patients receiving pelvic external beam radiotherapy were retrospectively analyzed. 30, 21 and 14 patients were treated with no-immobilization with a leg separator, whole body vacuum bag cushion (VBC) and six point aquaplast immobilization system, respectively. The systematic error, random error and the planning target volume (PTV) margins were calculated for all the three techniques and statistically analyzed., Results: The systematic errors were the highest in the VBC and random errors were the highest in the aquaplast group. Both systematic and random errors were the lowest in patients treated with no-immobilization. 3D Systematic error (mm, mean ± 1SD) was 4.31 ± 3.84, 3.39 ± 1.71 and 2.42 ± 0.97 for VBC, aquaplast and no-immobilization, respectively. 3D random error (mm, 1SD) was 2.96, 3.59 and 1.39 for VBC, aquaplast and no-immobilization, respectively. The differences were statistically significant between all the three groups. The calculated PTV margins were the smallest for the no-immobilization technique with 4.56, 4.69 and 4.59 mm, respectively, in x , y and z axes, respectively., Conclusions: Among the three techniques, no-immobilization technique with leg separator was the most reproducible technique with the smallest PTV margins. For obvious reasons, this technique is the least time consuming and most economically viable in developing countries.

Purpose: To evaluate different registration methods, setup margins and number of corrections for CBCT-based position verification for oesophageal cancer and to evaluate anatomical changes during the course of radiotherapy treatment., Methods: From 50 patients, 440 CBCT-scans were registered automatically using a soft tissue or bone registration algorithm and compared to the clinical match. Moreover, relevant anatomical changes were monitored. A sub-analysis was performed to evaluate if tumour location influenced setup variations. Margin calculation was performed and the number of setup corrections was estimated. Results were compared to a patient group previously treated with MV-EPID based position verification., Results: CBCT-based setup variations were smaller than EPID-based setup variations, resulting in smaller setup margins of 5.9 mm (RL), 7.5 mm (CC) and 4.7 mm (AP) versus 6.0 mm, 7.8 mm and 5.5 mm, respectively. A reduction in average number of setup corrections per patient was found from 0.75 to 0.36. From all automatically registered CBCT-scans, a clipbox around PTV and vertebras combined with soft tissue registration resulted in the smallest setup margins of 5.9 mm (RL), 7.7 mm (CC), 4.8 mm (AP) and smallest average number of corrections of 0.38. For distally located tumours, a setup margin of 7.7 mm (CC) was required compared to 5.6 mm for proximal tumours. Reduction of GTV volume, heart volume and change in diaphragm position were observed in 16, 10 and 15 patients, respectively., Conclusions: CBCT-based set-up variations are smaller than EPID-based variations and vary according to tumour location. When using kV-CBCT a large variety of anatomical changes is revealed, which cannot be observed with MV-EPID., (© 2017 The Authors. Published by Elsevier Ireland Ltd on behalf of European Society for Radiotherapy & Oncology.)