European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus recommendations on patient selection and dose and fractionation for external beam radiotherapy in early breast cancer.

High-quality randomised clinical trials testing moderately fractionated breast radiotherapy have clearly shown that local control and survival is at least as effective as with 2 Gy daily fractions with similar or reduced normal tissue toxicity. Fewer treatment visits are welcomed by patients and their families, and reduced fractions produce substantial savings for health-care systems. Implementation of hypofractionation, however, has moved at a slow pace. The oncology community have now reached an inflection point created by new evidence from the FAST-Forward five-fraction randomised trial and catalysed by the need for the global radiation oncology community to unite during the COVID-19 pandemic and rapidly rethink hypofractionation implementation. The aim of this paper is to support equity of access for all patients to receive evidence-based breast external beam radiotherapy and to facilitate the translation of new evidence into routine daily practice. The results from this European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus state that moderately hypofractionated radiotherapy can be offered to any patient for whole breast, chest wall (with or without reconstruction), and nodal volumes. Ultrafractionation (five fractions) can also be offered for non-nodal breast or chest wall (without reconstruction) radiotherapy either as standard of care or within a randomised trial or prospective cohort. The consensus is timely; not only is it a pragmatic framework for radiation oncologists, but it provides a measured proposal for the path forward to influence policy makers and empower patients to ensure equity of access to evidence-based radiotherapy.

No changes in myocardial perfusion following radiation therapy of left-sided breast cancer: A positron emission tomography study.

BACKGROUND: Adjuvant radiation therapy (RT) for breast cancer has improved overall survival. However, incidental exposure of the heart has been linked to development of radiation-induced heart disease. The aim of this study was, in a cohort of asymptomatic post-irradiation breast cancer patients, to investigate changes in myocardial blood flow (MBF) and presence of perfusion defects in myocardial perfusion positron-emission-tomography (PET) in the irradiated myocardium. METHODS AND RESULTS: Twenty patients treated with RT for left-sided breast cancer underwent 13N-ammonia myocardial perfusion PET 7(± 2) years after breath adapted RT to a total dose of 48 Gy given in 24 fractions. No differences in rest or stress MBF were noted between the irradiated and non-irradiated myocardium (1.29 (± 0.29) vs 1.33 (± 0.29) mL/g/min, ns; 2.74 (± 0.59) vs 2.78 (± 0.66) mL/g/min, ns, respectively). One patient demonstrated a myocardial perfusion defect localized in the irradiated anterior wall myocardium. CONCLUSION: Although limited by a small sample size, early signs of cardiac injury detected by NH3 myocardial perfusion PET was at least not frequent in our cohort of patients treated with a modern RT technique for left-sided breast cancer, even 7 years after treatment. The findings however, may not rule out subsequent development of myocardial injury.

Tumour control probability after Ruthenium-106 brachytherapy for choroidal melanomas.

Purpose: Ruthenium-106 (Ru-106) brachytherapy is a common eye-preserving treatment for choroidal melanomas. However, a dose-response model describing the relationship between the actual delivered tumour dose and tumour control has, to the best of our knowledge, not previously been quantified for Ru-106 brachytherapy; we aimed to rectify this.Material and methods: We considered consecutive patients with primary choroidal melanomas, treated with Ru-106 brachytherapy (2005-2014). Dosimetric plans were retrospectively recreated using 3D image-guided planning software. Pre-treatment fundus photographies were used to contour the tumour; post-treatment photographies to determine the accurate plaque position. Patient and tumour characteristics, treatment details, dose volume histograms, and clinical outcomes were extracted. Median follow-up was 5.0 years. The relationship between tumour dose and risk of local recurrence was examined using multivariate Cox regression modelling, with minimum physical tumour dose (D99%) as primary dose metric.Results: We included 227 patients with median tumour height and largest base dimension of 4 mm (range 1-12, IQR 3-6) and 11 mm (range 4-23, IQR 9-13). The estimated 3 year local control was 82% (95% CI 77-88). Median D99% was 105 Gy (range 6-783, IQR 65-138); this was the most significant factor associated with recurrence (p < .0001), although tumour height, combined TTT and Ru-106 brachytherapy, and sex were also significant. The hazard ratio (HR) for a 10 Gy increase in D99% was 0.87 (95% CI 0.82-0.93). Using biological effective dose in the model resulted in no substantial difference in dose dependence estimates. Robustness cheques with D1-99% showed D99% to be the most significant dose metric for local recurrence.Conclusion: The minimum tumour dose correlated strongly with risk of tumour recurrence, with 100 Gy needed to ensure at least 84% local control at 3 years.

Biological optimization for mediastinal lymphoma radiotherapy - a preliminary study.

Purpose: In current radiotherapy (RT) planning and delivery, population-based dose-volume constraints are used to limit the risk of toxicity from incidental irradiation of organs at risks (OARs). However, weighing tradeoffs between target coverage and doses to OARs (or prioritizing different OARs) in a quantitative way for each patient is challenging. We introduce a novel RT planning approach for patients with mediastinal Hodgkin lymphoma (HL) that aims to maximize overall outcome for each patient by optimizing on tumor control and mortality from late effects simultaneously.Material and Methods: We retrospectively analyzed 34 HL patients treated with conformal RT (3DCRT). We used published data to model recurrence and radiation-induced mortality from coronary heart disease and secondary lung and breast cancers. Patient-specific doses to the heart, lung, breast, and target were incorporated in the models as well as age, sex, and cardiac risk factors (CRFs). A preliminary plan of candidate beams was created for each patient in a commercial treatment planning system. From these candidate beams, outcome-optimized (O-OPT) plans for each patient were created with an in-house optimization code that minimized the individual risk of recurrence and mortality from late effects. O-OPT plans were compared to VMAT plans and clinical 3DCRT plans.Results: O-OPT plans generally had the lowest risk, followed by the clinical 3DCRT plans, then the VMAT plans with the highest risk with median (maximum) total risk values of 4.9 (11.1), 5.1 (17.7), and 7.6 (20.3)%, respectively (no CRFs). Compared to clinical 3DCRT plans, O-OPT planning reduced the total risk by at least 1% for 9/34 cases assuming no CRFs and 11/34 cases assuming presence of CRFs.Conclusions: We developed an individualized, outcome-optimized planning technique for HL. Some of the resulting plans were substantially different from clinical plans. The results varied depending on how risk models were defined or prioritized.

Long-term hospitalisation rates among 5-year survivors of Hodgkin lymphoma in adolescence or young adulthood: A nationwide cohort study.

In the present study, we report on the full range of physical diseases acquired by survivors of Hodgkin lymphoma diagnosed in adolescence or young adulthood. In a Danish nationwide population-based cohort study, 1,768 five-year survivors of Hodgkin lymphoma diagnosed at ages 15-39 years during 1943-2004 and 228,447 comparison subjects matched to survivors on age and year of birth were included. Hospital discharge diagnoses and bed-days during 1977-2010 were obtained from the Danish Patient Register for 145 specific disease categories gathered in 14 main diagnostic groups. The analysis was conducted separately on three subcohorts of survivors, that is, survivors diagnosed 1943-1976 for whom we had no information on rehospitalisation for Hodgkin lymphoma and survivors diagnosed 1977-2004, split into a subcohort with no expected relapses and a subcohort for whom a rehospitalisation for Hodgkin lymphoma indicated a relapse. The overall standardised hospitalisation rate ratios (RRs) were 2.0 [95% confidence interval (CI), 1.9-2.1], 1.5 (1.4-1.6) and 2.9 (2.6-3.1) respectively, and the corresponding RRs for bed-days were 3.5 (3.4-3.5), 1.8 (1.8-1.9) and 10.4 (10.3-10.6). Highest RRs were seen for nonmalignant haematological conditions (RR: 2.6; 3.1 and 9.7), malignant neoplasms (RR: 3.2; 2.5 and 4.7) and all infections combined (RR: 2.5; 2.2 and 5.3). Survivors of Hodgkin lymphoma in adolescence or young adulthood are at increased risk for a wide range of diseases that require hospitalisation. The risk depends on calendar period of treatment and on whether the survivors were rehospitalised for Hodgkin lymphoma, and thus likely had a relapse.

A modeling study of functional magnetic resonance imaging to individualize target definition of seminal vesicles for external beam radiotherapy.

BACKGROUND: Pre-treatment magnetic resonance imaging (MRI) can give patient-specific evaluation of suspected pathologically involved volumes in the seminal vesicles (SV) in prostate cancer patients. By targeting this suspicious volume we hypothesize that radiotherapy is more efficient without introducing more toxicity. In this study we evaluate the concept of using MRI-defined target volumes in terms of tumor control probability (TCP) and rectal normal tissue complication probability (NTCP). MATERIAL AND METHODS: Twenty-one high-risk prostate cancer patients were included. Pre-treatment CT images, T2 weighted (T2w) MRI and two multi-parametric MRI were acquired. Overlap between a suspicious volume in the SV observed on T2w images and a suspicious volume observed on either multi-parametric MRI was assumed to reflect a true malignant region (named 'MRI positive'). In addition the entire SV on the CT-scan was delineated. Three treatment plans of 2 Gy ×39 fractions were generated per patient: one covering the MRI positive volume in SV and prostate with margin of 11 mm to the MRI positive in the SV and two plans covering prostate and SV using 11 and 7 mm SV margin, respectively. All plans were prescribed the same PTV mean dose. Rectal NTCP grade ≥2 was evaluated with the Lyman-Kutcher-Burman model and TCP was estimated by a logistic model using the combined MRI positive volume in SV and prostate as region-of-interest. RESULTS: Fourteen of twenty-one patients were classified as MRI positive, six of which had suspicious volumes in all three MRI modalities. On average TCP for the plan covering prostate and the MRI positive volume was 3% higher (up to 11%) than the two other plans which was statistically significant. The increased TCP was obtained without increasing rectal NTCP grade ≥2. CONCLUSIONS: Using functional MRI for individualized target delineation in the SV may improve the treatment outcome in radiotherapy of prostate cancer without increasing the rectal toxicity.

Interobserver delineation uncertainty in involved-node radiation therapy (INRT) for early-stage Hodgkin lymphoma: on behalf of the Radiotherapy Committee of the EORTC lymphoma group.

BACKGROUND AND PURPOSE: In early-stage classical Hodgkin lymphoma (HL) the target volume nowadays consists of the volume of the originally involved nodes. Delineation of this volume on a post-chemotherapy CT-scan is challenging. We report on the interobserver variability in target volume definition and its impact on resulting treatment plans. MATERIALS AND METHODS: Two representative cases were selected (1: male, stage IB, localization: left axilla; 2: female, stage IIB, localizations: mediastinum and bilateral neck). Eight experienced observers individually defined the clinical target volume (CTV) using involved-node radiotherapy (INRT) as defined by the EORTC-GELA guidelines for the H10 trial. A consensus contour was generated and the standard deviation computed. We investigated the overlap between observer and consensus contour [Sørensen-Dice coefficient (DSC)] and the magnitude of gross deviations between the surfaces of the observer and consensus contour (Hausdorff distance). 3D-conformal (3D-CRT) and intensity-modulated radiotherapy (IMRT) plans were calculated for each contour in order to investigate the impact of interobserver variability on each treatment modality. Similar target coverage was enforced for all plans. RESULTS: The median CTV was 120 cm3 (IQR: 95-173 cm3) for Case 1, and 255 cm3 (IQR: 183-293 cm3) for Case 2. DSC values were generally high (>0.7), and Hausdorff distances were about 30 mm. The SDs between all observer contours, providing an estimate of the systematic error associated with delineation uncertainty, ranged from 1.9 to 3.8 mm (median: 3.2 mm). Variations in mean dose resulting from different observer contours were small and were not higher in IMRT plans than in 3D-CRT plans. CONCLUSIONS: We observed considerable differences in target volume delineation, but the systematic delineation uncertainty of around 3 mm is comparable to that reported in other tumour sites. This report is a first step towards calculating an evidence-based planning target volume margin for INRT in HL.

Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold.

BACKGROUND: Long-term Hodgkin lymphoma (HL) survivors have an increased risk of late cardiac morbidity and secondary lung cancer after chemotherapy and mediastinal radiotherapy. In this prospective study we investigate whether radiotherapy with deep inspiration breath-hold (DIBH) can reduce radiation doses to the lungs, heart, and cardiac structures without compromising the target dose. PATIENTS AND METHODS: Twenty-two patients (14 female, 8 male), median age 30 years (18-65 years), with supra-diaphragmatic HL were enrolled and had a thoracic PET/CT with DIBH in addition to staging FDG-PET/CT in free breathing (FB) and a planning CT in both FB and DIBH. For each patient an involved-node radiotherapy plan was done for both DIBH and FB, and the doses to the lungs, heart, and female breasts were recorded prospectively. Mean doses to the heart valves and coronary arteries were recorded retrospectively. Patients were treated with the technique yielding the lowest doses to normal structures. RESULTS: Nineteen patients were treated with DIBH and three with FB. DIBH reduced the mean estimated lung dose by 2.0 Gy (median: 8.5 Gy vs. 7.2 Gy) (p < 0.01) and the mean heart dose by 1.4 Gy (6.0 Gy vs. 3.9 Gy) (p < 0.01) compared to FB. The lung and heart V20Gy were reduced with a median of 5.3% and 6.3%. Mean doses to the female breasts were equal with FB and DIBH. CONCLUSION: DIBH can significantly decrease the estimated mean doses to the heart and lungs without lowering the dose to the target in radiotherapy for patients with mediastinal HL.

Spatio-temporal stability of pre-treatment 18F-Fludeoxyglucose uptake in head and neck squamous cell carcinomas sufficient for dose painting.

BACKGROUND: The pre-treatment 18F-Fludeoxyglucose (FDG) avid subvolume of the tumor has shown promise as a potential target for dose painting in patients with in head and neck squamous cell carcinomas (HNSCC). PURPOSE: The purposes of this study are: 1) to assess the pre-treatment spatio-temporal variability of FDG PET/CT target volumes and 2) to assess the impact of this variability on dose distribution in dose painting plans in patients with HNSCC. MATERIAL AND METHODS: Thirty patients were enrolled and scanned twice, three days apart, days prior to treatment. Delineation of the FDG avid subvolume of the tumor and lymph nodes on both scans was performed by a specialist in nuclear medicine yielding GTVPET1 and GTVPET2 and segmentation based on SUV iso-contours were constructed yielding two metabolic target volumes, MTV1 and MTV2. Images were co-registered rigidly and dose painting plans with dose escalation up to 82 Gy to GTVPET1 were planned and GTVPET2 was copied from the co-registered images to the dose planning scan. Variation in dose to the target and modeled tumor control probability were assessed as measures of the impact of imaging variations in a dose painting scenario. RESULTS: Twenty-four patients were available for full analysis. The median mismatch between GTVPET1 and GTVPET2 was 14.2% (1.7 cm(3)). The median difference in dose to the FDG planning target volume was 0.3 Gy (PTVPET) and 0.4 Gy (PTVMTV). Median difference in the modeled tumor control probability (TCP) was < 0.2% and 23 of 24 patients had a difference in expected TCP < 1%. CONCLUSIONS: Pre-treatment FDG PET/CT target volumes were stable and day-to-day variability had no relevant impact on dose distribution and expected tumor control in dose painting plans.

Prescribing and evaluating target dose in dose-painting treatment plans.

BACKGROUND: Assessment of target dose conformity in multi-dose-level treatment plans is challenging due to inevitable over/underdosage at the border zone between dose levels. Here, we evaluate different target dose prescription planning aims and approaches to evaluate the relative merit of such plans. A quality volume histogram (QVH) tool for history-based evaluation is proposed. MATERIAL AND METHODS: Twenty head and neck cancer dose-painting plans with five prescription levels were evaluated, as well as clinically delivered simultaneous integrated boost (SIB) plans from 2010 and 2012. The QVH tool was used for target dose comparison between groups of plans, and to identify and improve a suboptimal dose-painting plan. RESULTS: Comparison of 2010 and 2012 treatment plans with the QVH tool demonstrated that 2012 plans have decreased underdosed volume at the expense of increased overdosed volume relative to the 2010 plans. This shift had not been detected previously. One suboptimal dose-painting plan was compared to the 'normal zone' of the QVH tool and could be improved by re-optimization. CONCLUSION: The QVH tool provides a method to assess target dose conformity in dose-painting and multi-dose-level plans. The tool can be useful for quality assurance of multi-center trials, and for visualizing the development of treatment planning in routine clinical practice.

Optimizing the radiation therapy dose prescription for pediatric medulloblastoma: minimizing the life years lost attributable to failure to control the disease and late complication risk.

BACKGROUND: A mathematical framework is presented for simultaneously quantifying and evaluating the trade-off between tumor control and late complications for risk-based radiation therapy (RT) decision-support. To demonstrate this, we estimate life years lost (LYL) attributable to tumor recurrence, late cardiac toxicity and secondary cancers for standard-risk pediatric medulloblastoma (MB) patients and compare the effect of dose re-distribution on a common scale. METHODS: Total LYL were derived, based on the LYL attributable to radiation-induced late complications and the LYL from not controlling the primary disease. We compared the estimated LYL for three different treatments in 10 patients: 1) standard 3D conformal RT; 2) proton therapy; 3) risk-adaptive photon treatment lowering the dose to part of the craniospinal (CS) target volume situated close to critical risk organs. RESULTS: Late toxicity is important, with 0.75 LYL (95% CI 0.60-7.2 years) for standard uniform 24 Gy CS irradiation. However, recurrence risk dominates the total LYL with 14.2 years (95% CI 13.4-16.6 years). Compared to standard treatment, a risk-adapted strategy prescribing 12 Gy to the spinal volume encompassing the 1st-10th thoracic vertebrae (Th1-Th10), and 36 Gy to the remaining CS volume, estimated a LYL reduction of 0.90 years (95% CI -0.18-2.41 years). Proton therapy with 36 Gy to the whole CS volume was associated with significantly fewer LYL compared to the risk-adapted photon strategies, with a mean LYL difference of 0.50 years (95% CI 0.25-2.60 years). CONCLUSIONS: Optimization of RT prescription strategies considering both late complications and the risk of recurrence, an all-cause mortality dose painting approach, was demonstrated. The risk-adapted techniques compared favorably to the standard, and although in this context, the gain is small compared to estimated uncertainty, this study demonstrates a framework for all-cause mortality risk estimation, rather than evaluates direct clinical applicability of risk-adapted strategies.

Reduced lung dose and improved inspiration level reproducibility in visually guided DIBH compared to audio coached EIG radiotherapy for breast cancer patients.

INTRODUCTION: Patients with left-sided breast cancer with lymph node involvement have routinely been treated with enhanced inspiration gating (EIG) for a decade at our institution. In a transition from EIG to deep inspiration breath hold (DIBH) we compared the two techniques with focus on target coverage, dose to organs at risk and reproducibility of the inspiration level (IL). MATERIAL AND METHODS: Twenty-four patients were computed tomography (CT) scanned with EIG and DIBH. For DIBH we used visual feedback and for EIG audio coaching, both during scan and treatment. Treatment plans for 50 Gy over 25 fractions were calculated. Seventeen of the patients were included in the analysis of reproducibility. They were audio coached for one minute before beam-on in DIBH at nine treatment sessions. These respiration curves were analysed with average maximum IL and standard deviation (SD) for the EIG part of the respiratory signal, and mean IL and SD for the DIBH. Comparison of dosimetric and respiration parameters were performed with the Wilcoxon signed rank-sum test. RESULTS: In DIBH, the ipsilateral lung volume increased further compared to EIG (p < 0.0004, mean increase 11%). This lead to a 9% mean reduction (p = 0.002) of the ipsilateral lung volume receiving 20 Gy (V20 Gy). We found no other significant dosimetric differences between the two methods. The reproducibility of the IL was better with the DIBH method, observed as a significantly smaller SD in most patients (p < 0.04 for 16 of 17 patients). CONCLUSION: The DIBH method resulted in a significantly larger lung volume and lower ipsilateral lung V20 Gy compared to EIG. The IL for visually guided DIBH was more reproducible than audio-coached EIG. Based on these findings, the DIBH technique is our new breathing adaptation standard for radiotherapy of patients with left-sided breast cancer with lymph node involvement.

The effect on esophagus after different radiotherapy techniques for early stage Hodgkin's lymphoma.

INTRODUCTION: The cure rate of early stage Hodgkin's lymphoma (HL) is excellent; investigating the late effects of treatment is thus important. Esophageal toxicity is a known side effect in patients receiving radiotherapy (RT) to the mediastinum, although little is known of this in HL survivors. This study investigates the dose to the esophagus in the treatment of early stage HL using different RT techniques. Estimated risks of early esophagitis, esophageal stricture and cancer are compared between treatments. MATERIAL AND METHODS: We included 46 patients ≥ 15 years with supradiaphragmatic, clinical stage I-II HL, who received chemotherapy followed by involved node RT (INRT) to 30.6 Gy at our institution. INRT was planned with three-dimensional conformal RT (3DCRT). For each patient a volumetric modulated arc therapy (VMAT), proton therapy (PT) and mantle field (MF) treatment plan was simulated. Mean, maximum and minimum dose to the esophagus were extracted from the treatment plans. Risk estimates were based on dose-response models from clinical series with long-term follow-up. Statistical analyses were performed with repeated measures ANOVA using Bonferroni corrections. RESULTS: Mean dose to the esophagus was 16.4, 16.4, 14.7 and 34.2 Gy (p < 0.001) with 3DCRT, VMAT, PT and MF treatment, respectively. No differences were seen in the estimated risk of developing esophagitis, stricture or cancer with 3DCRT compared to VMAT (p = 1.000, p = 1.000, p = 0.356). PT performed significantly better with the lowest risk estimates on all parameters compared to the photon treatments, except compared to 3DCRT for stricture (p = 0.066). On all parameters the modern techniques were superior to MF treatment (p < 0.001). CONCLUSIONS: The estimated dose to the esophagus and the corresponding estimated risks of esophageal complications are decreased significantly with highly conformal RT compared to MF treatment. The number of patients presenting with late esophageal side effects will, thus, likely be minimal in the future.

Stability of percutaneously implanted markers for lung stereotactic radiotherapy.

The purpose of this study was to evaluate the stability of complex markers implanted into lung tumors throughout a course of stereotactic body radiotherapy (SBRT). Fifteen patients referred for lung SBRT were prospectively included. Radio-opaque markers were implanted percutaneously, guided by computed tomography (CT). Deep inspiration breath-hold CT scans (BHCT) were acquired at planning and on three treatment days. The treatment days' BHCTs were registered to the planning BHCT. Intraobserver uncertainty in both tumor and marker registration was determined. Deviations in the difference between tumor and marker-based image registrations of the BHCT scans during treatment quantified the marker stability. Marker position deviation relative to tumor position of less than 2 mm in all three dimensions was considered acceptable for treatment delivery precision. Intra observer uncertainties for image registration in the left-right (LR), anterior-posterior (AP), craniocaudal (CC) directions and three-dimensional vector (3D) were 0.9 mm, 0.9 mm, 1.0 mm, and 1.1 mm (SD) for tumor registration and 0.3 mm, 0.5 mm, 0.7 mm, and 0.7 mm (SD) for marker registration. Mean 3D differences for tumor registrations on all days were significantly larger than for 3D marker registrations (p = 0.007). Overall median differences between tumor and marker position were 0.0 mm (range -2.9 to 2.6 mm) in LR, 0.0 mm (-1.8 to 1.5 mm) in AP, and -0.2 mm (-2.6 to 2.8 mm) in CC directions. Four patients had deviations exceeding 2 mm in one or more registrations throughout the SBRT course. This is the first study to evaluate stability of complex markers implanted percutaneously into lung tumors for image guidance in SBRT. We conclude that the observed stability of marker position within the tumor indicates that complex markers can be used as surrogates for tumor position during a short course of SBRT as long as the uncertainties related to their position within the tumor are incorporated into the planning target volume.

A survey of practice patterns for adaptive particle therapy for interfractional changes.

Background and purpose: Anatomical changes may compromise the planned target coverage and organs-at-risk dose in particle therapy. This study reports on the practice patterns for adaptive particle therapy (APT) to evaluate current clinical practice and wishes and barriers to further implementation. Materials and methods: An institutional questionnaire was distributed to PT centres worldwide (7/2020-6/2021) asking which type of APT was used, details of the workflow, and what the wishes and barriers to implementation were. Seventy centres from 17 countries participated. A three-round Delphi consensus analysis (10/2022) among the authors followed to define recommendations on required actions and future vision. Results: Out of the 68 clinically operational centres, 84% were users of APT for at least one treatment site with head and neck being most common. APT was mostly performed offline with only two online APT users (plan-library). No centre used online daily re-planning. Daily 3D imaging was used for APT by 19% of users. Sixty-eight percent of users had plans to increase their use or change their technique for APT. The main barrier was "lack of integrated and efficient workflows". Automation and speed, reliable dose deformation for dose accumulation and higher quality of in-room volumetric imaging were identified as the most urgent task for clinical implementation of online daily APT. Conclusion: Offline APT was implemented by the majority of PT centres. Joint efforts between industry research and clinics are needed to translate innovations into efficient and clinically feasible workflows for broad-scale implementation of online APT.

Proton linear energy transfer and variable relative biological effectiveness for adolescent patients with Hodgkin lymphoma.

Objectives: Proton therapy has a theoretical dosimetric advantage due to the Bragg peak, but the linear energy transfer (LET), and therefore the relative biological effectiveness (RBE), increase at the end of range. For patients with Hodgkin lymphoma, the distal edge of beam is often located within or close to the heart, where elevated RBE would be of potential concern. The purpose of this study was to investigate the impact of RBE and the choice of beam arrangement for adolescent patients with mediastinal Hodgkin lymphoma. Methods: For three previously treated adolescent patients, proton plans with 1-3 fields were created to a prescribed dose of 19.8 Gy (RBE) in 11 fractions (Varian Eclipse v13.7), assuming an RBE of 1.1. Plans were recalculated using Monte-Carlo (Geant4 v10.3.3/Gate v8.1) to calculate dose-averaged LET. Variable RBE-weighted dose was calculated using the McNamara model, assuming an α/ß ratio of 2 Gy for organs-at-risk. Results: Although the LET decreased as the number of fields increased, the difference in RBE-weighted dose (Δdose) to organs-at-risk did not consistently decrease. Δdose values varied by patient and organ and were mostly of the order of 0-3 Gy (RBE), with a worst-case of 4.75 Gy (RBE) in near-maximum dose to the left atrium for one plan. Conclusions: RBE-weighted doses to organs-at-risk are sensitive to the choice of RBE model, which is of particular concern for the heart. Advances in knowledge: There is a need to remain cautious when evaluating proton plans for Hodgkin lymphoma, especially when near-maximum doses to organs-at-risk are considered.

Physics Considerations for Evaluation of Dose for Dose-Response Models of Pediatric Late Effects From Radiation Therapy.

PURPOSE: We describe the methods used to estimate the accuracy of dosimetric data found in literature sources used to construct the Pediatric Normal Tissue Effects in the Clinic (PENTEC) dose-response models, summarize these findings of each organ-specific task force, describe some of the dosimetric challenges and the extent to which these efforts affected the final modeling results, and provide guidance on the interpretation of the dose-response results given the various dosimetric uncertainties. METHODS AND MATERIALS: Each of the PENTEC task force medical physicists reviewed all the journal articles used for dose-response modeling to identify, categorize, and quantify dosimetric uncertainties. These uncertainties fell into 6 broad categories. A uniform nomenclature was developed for describing the "dosimetric quality" of the articles used in the PENTEC reviews. Among the multidisciplinary experts in the PENTEC effort, the medical physicists were charged with the dosimetric evaluation, as they are most expert in this subject. RESULTS: The percentage dosimetric uncertainty was estimated for each late effect endpoint for all PENTEC organ reports. Twelve specific sources of dose uncertainty were identified related to the 6 broad categories. The most common reason for organ dose uncertainty was that prescribed dose rather than organ dose was reported. Percentage dose uncertainties ranged from 5% to 200%. Systematic uncertainties were used to correct the dose component of the models. Random uncertainties were also described in each report and in some cases used to modify dose axis error bars. In addition, the potential effects of dose binning were described. CONCLUSIONS: PENTEC reports are designed to provide guidance to radiation oncologists and treatment planners for organ dose constraints. It is critical that these dose constraint recommendations are as accurate as possible, acknowledging the large error bars for many. Achieving this accuracy is important as it enables clinicians to better balance target dose coverage with risk of late effects. Evidence-based dose constraints for pediatric patients have been lacking and, in this regard, PENTEC fills an important unmet need. One must be aware of the limitations of our recommendations, and that for some organ systems, large uncertainties exist in the dose-response model because of clinical endpoint uncertainty, dosimetric uncertainty, or both.

Proton Beam Therapy in the Oligometastatic/Oligorecurrent Setting: Is There a Role? A Literature Review.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS) with conventional photon radiotherapy (XRT) are well-established treatment options for selected patients with oligometastatic/oligorecurrent disease. The use of PBT for SABR-SRS is attractive given the property of a lack of exit dose. The aim of this review is to evaluate the role and current utilisation of PBT in the oligometastatic/oligorecurrent setting. METHODS: Using Medline and Embase, a comprehensive literature review was conducted following the PICO (Patients, Intervention, Comparison, and Outcomes) criteria, which returned 83 records. After screening, 16 records were deemed to be relevant and included in the review. RESULTS: Six of the sixteen records analysed originated in Japan, six in the USA, and four in Europe. The focus was oligometastatic disease in 12, oligorecurrence in 3, and both in 1. Most of the studies analysed (12/16) were retrospective cohorts or case reports, two were phase II clinical trials, one was a literature review, and one study discussed the pros and cons of PBT in these settings. The studies presented in this review included a total of 925 patients. The metastatic sites analysed in these articles were the liver (4/16), lungs (3/16), thoracic lymph nodes (2/16), bone (2/16), brain (1/16), pelvis (1/16), and various sites in 2/16. CONCLUSIONS: PBT could represent an option for the treatment of oligometastatic/oligorecurrent disease in patients with a low metastatic burden. Nevertheless, due to its limited availability, PBT has traditionally been funded for selected tumour indications that are defined as curable. The availability of new systemic therapies has widened this definition. This, together with the exponential growth of PBT capacity worldwide, will potentially redefine its commissioning to include selected patients with oligometastatic/oligorecurrent disease. To date, PBT has been used with encouraging results for the treatment of liver metastases. However, PBT could be an option in those cases in which the reduced radiation exposure to normal tissues leads to a clinically significant reduction in treatment-related toxicities.

Prioritizing clinical trial quality assurance for photons and protons: A failure modes and effects analysis (FMEA) comparison.

BACKGROUND AND PURPOSE: The Global Clinical Trials RTQA Harmonization Group (GHG) set out to evaluate and prioritize clinical trial quality assurance. METHODS: The GHG compiled a list of radiotherapy quality assurance (QA) tests performed for proton and photon therapy clinical trials. These tests were compared between modalities to assess whether there was a need for different types of assessments per modality. A failure modes and effects analysis (FMEA) was performed to assess the risk of each QA failure. RESULTS: The risk analysis showed that proton and photon therapy shared four out of five of their highest-risk failures (end-to-end anthropomorphic phantom test, phantom tests using respiratory motion, pre-treatment patient plan review of contouring/outlining, and on-treatment/post-treatment patient plan review of dosimetric coverage). While similar trends were observed, proton therapy had higher risk failures, driven by higher severity scores. A sub-analysis of occurrence × severity scores identified high-risk scores to prioritize for improvements in RTQA detectability. A novel severity scaler was introduced to account for the number of patients affected by each failure. This scaler did not substantially alter the ranking of tests, but it elevated the QA program evaluation to the top 20th percentile. This is the first FMEA performed for clinical trial quality assurance. CONCLUSION: The identification of high-risk errors associated with clinical trials is valuable to prioritize and reduce errors in radiotherapy and improve the quality of trial data and outcomes, and can be applied to optimize clinical radiotherapy QA.