Cosmetic outcome in patients with early stage breast cancer after accelerated partial breast irradiation using intraoperative or external beam radiotherapy.

Purpose: The aim of this study is to evaluate the cosmetic outcome among early stage breast cancer patients who underwent accelerated partial breast irradiation with either intraoperative electron radiotherapy (IOERT) or photon external beam radiotherapy (EB-APBI). Materials and methods: This prospective multicenter cohort study enrolled women aged 60 years and older who underwent breast-conserving therapy. Following breast-conserving surgery, patients were treated with either IOERT or EB-APBI. Cosmetic outcome was evaluated over a 5 year follow-up period using both subjective scoring by patients and physicians, as well as objective scoring using BCCT.core software. Differences between treatments over time were described with mixed model analyses. Results: A total of 241 patients treated with IOERT and 164 patients treated with EB-APBI were eligible for cosmetic analysis. In both groups, the majority of patients reported a satisfactory cosmetic outcome, with no significant differences between treatments over time (p = 0.538). This was also observed by physicians, with satisfactory outcomes ranging from 94 % (170/181) to 91 % (69/76) over time in the IOERT group and from 93 % (124/133) to 95 % (54/57) in the EB-APBI group (p = 0.579). BCCT.core analysis returned satisfactory cosmetic outcomes in 75 % (54/72) of the IOERT patients at 3 years and in 77 % (20/26) at 5 years. These numbers were 86 % (72/84) and 90 % (36/40) for the EB-APBI patients, with no significant differences between treatment over time (p = 0.834). Conclusion: Regarding the cosmetic results, IOERT and EB-APBI yield comparable and satisfactory outcomes over 5 years follow-up in the treatment of early stage breast cancer.

External validation of the lung-molGPA to predict survival in patients treated with stereotactic radiotherapy for brain metastases of non-small cell lung cancer.

BACKGROUND: In the era of personalized medicine, individualized prognostic models with tumor characteristics are needed to inform patients about survival. Before clinical use, external validation of such models by an independent group is needed. An updated version of the graded prognostic assessment (GPA) estimates survival in patients with brain metastases (BMs) of non-small cell lung cancer (NSCLC). This is the first external validation of the updated Lung-molGPA in patients treated with stereotactic radiotherapy (SRT) for one or more BMs. MATERIALS AND METHODS: Patients treated with SRT for BMs from NSCLC adenocarcinoma were retrospectively included. GPA score was calculated for each patient based on six prognostic factors including age, Karnofsky Performance Status, number of BMs, extracranial metastases, EGFR/ALK status, and PD-L1 expression. Kaplan-Meier analysis evaluated survival probability. Impact of individual prognostic factors on survival was assessed by univariate and multivariate analyses using the Cox proportional hazard model. Predictive performance was evaluated using discrimination (C-statistic) and calibration (Brier test). RESULTS: The cohort (n = 241) was divided into four prognostic groups. Overall median survival was 15 months. Predicted and observed median survival were similar between the original and validation cohorts, apart from the most favorable prognostic group. With adequate C-statistics and Brier scores, the Lung-molGPA provided accurate survival predictions. CONCLUSION: The Lung-molGPA accurately predicted survival in our European population, except for an overestimation of survival in the small most favorable prognostic group. This prognostic model was externally validated and is therefore useful for counseling of patients with BMs of NSCLC adenocarcinoma.

A taskforce for national improvement of innovation implementation in radiotherapy.

BACKGROUND AND PURPOSE: Previous research among Dutch radiotherapy centres (RTCs) showed that 69% of innovations was simultaneously implemented in 7/19 centres, with a success rate of 51%. However, no structure to share lessons learned about the implementation process existed. Therefore, a national Taskforce Implementation (TTI) was raised to stimulate efficient implementation of innovations. The aim of the current study was to develop and pilot-evaluate a website for facilitating mutual learning on implementation issues. MATERIAL AND METHODS: First, we made an inventory in all Dutch RTCs on their 10 most valuable innovations between 2019 and 2022. In-depth interviews, structured according to the Consolidated Framework for Implementation Research, were performed on the four most mentioned topics. A website was built, and pilot evaluated 1 year after the launch, using a qualitative survey amongst the TTI members. RESULTS: In 13/18 centres, 19 interviews were conducted on 1) automation, 2) patient participation, 3) adaptive radiotherapy 4) surface guided radiotherapy and tracking. Most innovations (13/16) were implemented with a delay, with many comparable challenges: e.g. shortage of personnel (7/16) and prioritization of projects (9/16). The website allows users to upload and search for projects, including implementation experiences. After 1 year, 14 projects were uploaded. The qualitative evaluation was largely positive with room for improvement, i.e.75 % would recommend the website to others. CONCLUSION: This study showed that RTCs experience comparable challenges when implementing innovations, thereby underlining the need for a platform to share implementation-lessons learned. The first concept of this platform was evaluated positively.

ESTRO-ACROP guideline: Recommendations on implementation of breath-hold techniques in radiotherapy.

The use of breath-hold techniques in radiotherapy, such as deep-inspiration breath hold, is increasing although guidelines for clinical implementation are lacking. In these recommendations, we aim to provide an overview of available technical solutions and guidance for best practice in the implementation phase. We will discuss specific challenges in different tumour sites including factors such as staff training and patient coaching, accuracy, and reproducibility. In addition, we aim to highlight the need for further research in specific patient groups. This report also reviews considerations for equipment, staff training and patient coaching, as well as image guidance for breath-hold treatments. Dedicated sections for specific indications, namely breast cancer, thoracic and abdominal tumours are also included.

Excessive esophageal toxicity in patients with locally advanced non-small cell lung cancer treated with concurrent hypofractionated chemoradiotherapy and 3-weekly platinum doublet chemotherapy.

Introduction: Concurrent chemoradiation followed by immunotherapy is the standard of care for patients with stage III non-small cell lung cancer (NSCLC). Prior to the introduction of adjuvant immunotherapy, we treated patients with stage III NSCLC with concurrent platinum doublet chemotherapy and 66 Gy in 24 fractions. We determined the toxicity of this treatment. Methods: A retrospective observational study was performed in a cohort of patients with stage III NSCLC, <70 years old, and WHO performance score 0-1. Patients were treated with concurrent platinum doublet chemotherapy and 66 Gy in 24 fractions. All patients were staged with a PET-scan and brain MRI-scan. Toxicity was scored using the common criteria for adverse events (CTCAE v4.03). Results: Between 2012 and 2017, 41 patients were treated with mildly hypofractionated radiotherapy and platinum doublet chemotherapy. The median follow-up was 4.7 years. The median age was 57 and 58% of patients were male. The majority of patients had stage IIIB disease (68%). The median total Gross Tumor Volume (GTV) was 104 cc (range: 15-367 cc). The median lymph node GTV was 59 cc (10-341 cc). Five patients died: four due to an esophagus perforation or fistula, and one due to pulmonary bleeding. Grade ≥ 3 esophageal toxicity occurred in 16 patients. Five patients had late grade ≥ 3 esophageal toxicity (12%). The median overall survival was 19 months. Conclusion: Toxicity was unexpectedly high in patients with stage III NSCLC (WHO 0-1) after concurrent platinum doublet chemotherapy and 66 Gy in 24 fractions.

Development and evaluation of an automated EPTN-consensus based organ at risk atlas in the brain on MRI.

BACKGROUND AND PURPOSE: During radiotherapy treatment planning, avoidance of organs at risk (OARs) is important. An international consensus-based delineation guideline was recently published with 34 OARs in the brain. We developed an MR-based OAR autosegmentation atlas and evaluated its performance compared to manual delineation. MATERIALS AND METHODS: Anonymized cerebral T1-weighted MR scans (voxel size 0.9 × 0.9 × 0.9 mm3) were available. OARs were manually delineated according to international consensus. Fifty MR scans were used to develop the autosegmentation atlas in a commercially available treatment planning system (Raystation®). The performance of this atlas was tested on another 40 MR scans by automatically delineating 34 OARs, as defined by the 2018 EPTN consensus. Spatial overlap between manual and automated delineations was determined by calculating the Dice similarity coefficient (DSC). Two radiation oncologists determined the quality of each automatically delineated OAR. The time needed to delineate all OARs manually or to adjust automatically delineated OARs was determined. RESULTS: DSC was ≥ 0.75 in 31 (91 %) out of 34 automated OAR delineations. Delineations were rated by radiation oncologists as excellent or good in 29 (85 %) out 34 OAR delineations, while 4 were rated fair (12 %) and 1 was rated poor (3 %). Interobserver agreement between the radiation oncologists ranged from 77-100 % per OAR. The time to manually delineate all OARs was 88.5 minutes, while the time needed to adjust automatically delineated OARs was 15.8 minutes. CONCLUSION: Autosegmentation of OARs enables high-quality contouring within a limited time. Accurate OAR delineation helps to define OAR constraints to mitigate serious complications and helps with the development of NTCP models.

Accelerated Partial Breast Irradiation Using External Beam or Intraoperative Electron Radiation Therapy: 5-Year Oncological Outcomes of a Prospective Cohort Study.

PURPOSE: To evaluate the ipsilateral breast tumor recurrence (IBTR) after 2 accelerated partial breast irradiation (APBI) techniques (intraoperative electron radiation therapy [IOERT] and external beam APBI [EB-APBI]) in patients with early-stage breast cancer. METHODS AND MATERIALS: Between 2011 and 2016, women ≥60 years of age with breast carcinoma or Ductal Carcinoma In Situ (DCIS) of ≤30 mm and cN0 undergoing breast-conserving therapy were included in a 2-armed prospective multicenter cohort study. IOERT (1 × 23.3 Gy prescribed at the 100% isodose line) was applied in 1 hospital and EB-APBI (10 × 3.85 Gy daily) in 2 other hospitals. The primary endpoint was IBTR (all recurrences in the ipsilateral breast irrespective of localization) at 5 years after lumpectomy. A competing risk model was used to estimate the cumulative incidences of IBTR, which were compared using Fine and Gray's test. Secondary endpoints were locoregional recurrence rate, distant recurrence, disease-specific survival and overall survival. Univariate Cox regression models were estimated to identify risk factors for IBTR. Analyses were performed of the intention to treat (ITT) population (IOERT n = 305; EB-APBI n = 295), and sensitivity analyses were done of the per-protocol population (IOERT n = 270; EB-APBI n = 207). RESULTS: The median follow-up was 5.2 years (IOERT) and 5 years (EB-APBI). Cumulative incidence of IBTR in the ITT population at 5 years after lumpectomy was 10.6% (95% confidence interval, 7.0%-14.2%) after IOERT and 3.7% (95% confidence interval, 1.2%-5.9%) after EB-APBI (P = .002). The locoregional recurrence rate was significantly higher after IOERT than EB-APBI (12.1% vs 4.5%, P = .001). There were no differences between groups in other endpoints. Sensitivity analysis showed similar results. For both groups, no significant risk factors for IBTR were identified in the ITT population. In the per-protocol population, surgical margin status of the DCIS was the only significant risk factor for developing IBTR in both treatment groups. CONCLUSIONS: Ipsilateral breast tumor recurrences and locoregional recurrence rates were unexpectedly high in patients treated with IOERT, and acceptable in patients treated with EB-APBI.

Health-related quality of life of early-stage breast cancer patients after different radiotherapy regimens.

PURPOSE: To evaluate and compare health-related quality of life (HRQL) of women with early-stage breast cancer (BC) treated with different radiotherapy (RT) regimens. METHODS: Data were collected from five prospective cohorts of BC patients treated with breast-conserving surgery and different RT regimens: intraoperative RT (IORT, 1 × 23.3 Gy; n = 267), external beam accelerated partial breast irradiation (EB-APBI, 10 × 3.85 Gy; n = 206), hypofractionated whole breast irradiation(hypo-WBI, 16 × 2.67 Gy; n = 375), hypo-WBI + boost(hypo-WBI-B, 21-26 × 2.67 Gy; n = 189), and simultaneous WBI + boost(WBI-B, 28 × 2.3 Gy; n = 475). Women ≥ 60 years with invasive/in situ carcinoma ≤ 30 mm, cN0 and pN0-1a were included. Validated EORTC QLQ-C30/BR23 questionnaires were used to asses HRQL. Multivariable linear regression models adjusted for confounding (age, comorbidity, pT, locoregional treatment, systemic therapy) were used to compare the impact of the RT regimens on HRQL at 12 and 24 months. Differences in HRQL over time (3-24 months) were evaluated using linear mixed models. RESULTS: There were no significant differences in HRQL at 12 months between groups except for breast symptoms which were better after IORT and EB-APBI compared to hypo-WBI at 12 months (p < 0.001). Over time, breast symptoms, fatigue, global health status and role functioning were significantly better after IORT and EB-APBI than hypo-WBI. At 24 months, HRQL was comparable in all groups. CONCLUSION: In women with early-stage breast cancer, the radiotherapy regimen did not substantially influence long-term HRQL with the exception of breast symptoms. Breast symptoms are more common after WBI than after IORT or EB-APBI and improve slowly until no significant difference remains at 2 years posttreatment.

Atypical meningioma: patterns of postradiotherapy recurrences.

PURPOSE: There is no consensus on a target definition and optimal dose in radiotherapy for atypical meningioma (AM). Insight into the postradiotherapy recurrence pattern is needed for optimal target definition and local control. The objective was to describe the patterns of recurrence after postoperative or salvage radiotherapy in patients with AM. MATERIALS AND METHODS: A retrospective analysis was conducted of patients treated for intracranial AM with (fractionated) stereotactic radiotherapy (FSRT). The relationships between postradiotherapy recurrences, the dura and irradiated volume were established. Moreover, the dose prescriptions and fractionation schedules were converted to a reference to determine the relationship between dose and local control. RESULTS: The included patients received 57 (F)SRT treatments and 73 surgeries. Recurrent disease was found in 21 of 29 patients (72%) and after 39 of 57 (F)SRTs (68%). The median interval to first recurrence was 39.7 months. Of these recurrences, 25 were in-field, 11 were marginal, and 3 were out of field. In-field recurrence rates after biological equivalent doses < 60 Gy or ≥ 60 Gy were 50% and 21%. All recurrences were connected to the dura. Of the marginal recurrences, 64% were within 2 cm and 91% were within 3 cm of the volume receiving the prescribed dose. CONCLUSIONS: AM frequently recurs after radiotherapy. All postradiotherapy recurrences were connected to the dura. Most marginal recurrences occurred within 3 cm of the irradiated abnormal dura. The lowest rate of in-field recurrences occurred after equivalent doses of least 60 Gy in 2 Gy fractions suggesting a dose-effect relationship.

Impact of PTV margin reduction (2 mm to 0 mm) on pseudoprogression in stereotactic radiotherapy of solitary brain metastases.

PURPOSE: To determine the influence of PTV-margin (0 mm versus 2 mm) on the incidence of pseudoprogression (PP) and local tumour control (LC) in patients treated with stereotactic radiotherapy (SRT) for solitary brain metastases. METHODS: Patients were treated on Novalis LINAC. Three dose schedules were used depending on the PTV-size. The PTV-margin was 2-mm prior to 2015 and 0-mm thereafter. MRI-scans were made every three months including a perfusion MRI-scan when pseudoprogression was suspected. We examined the relation of pseudoprogression and local control with the size of PTV-margin. Besides this, the association of dose-volume data of the whole brain (minus GTV) and pseudoprogression was investigated. RESULTS: 121 patients were analyzed (2-mm margin in 84 patients; 0-mm margin in 37 patients). There was no difference in GTV (7.6 cc versus 9.1 cc p = 0.2). At 24 months there was no difference in incidence of pseudoprogression (49% and versus 33%, p = 0.5) and local control in the 2-mm and 0-mm group (82% and versus 79%, p = 1.0). The size of PTV-margin was not associated with PP. Both margin and volume of brain receiving 12 Gy (V12) were not associated with pseudoprogression in patients treated with single fraction. CONCLUSIONS: PTV-margin reduction did not reduce the incidence of pseudoprogression in LINAC-based-SRT for single brain metastases. We did not find a significant association of GTV-PTV margin or V12Gy with the incidence of pseudoprogression in solitary metastases treated with a single fraction. LC rates were similar, indicating margin reduction seems to be safe.

Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy.

Background: Stereotactic body radiation therapy (SBRT) results in high local control (LC) rates in patients with non-small cell lung cancer (NSCLC). For central lung tumors, risk-adapted fractionation schedules are used and underdosage to the Planned Target Volume (PTV) is often accepted to respect the dose constraints of the organs at risk in order to avoid high rates of toxicity. The purpose of this study was to analyze the effect of PTV underdosage and other possible prognostic factors on local- and disease control after SBRT in patients with central lung tumors.Material and Methods: Patients with centrally located NSCLC treated with SBRT were included. The doses were converted into biologically equivalent dose using α/ß-value of 10 Gy (BED10). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED10; (%)PTV < 100 BED10. Potential prognostic factors for LC and Disease Free Survival (DFS) were evaluated using Cox regression analysis.Results: Two hundred and twenty patients received ≤12 fractions of SBRT. LC-rates were 88% at 2 years and 81% at 3 years. Twenty-seven patients developed a local recurrence. Both the PTV < 100 BED10 and %PTV < 100 BED10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV1) were independently prognostic for LC. Disease progression was reported in 75 patients with DFS-rates of 66% at 2 years and 56% at 3 years. Disease recurrence was independent significantly associated with larger tumor diameter, lower lobe tumor location and decreased FEV1. Grade 4-5 toxicity was reported in 10 patients (8 with ultra-central tumors) and was fatal in at least 3 patients.Conclusion: Decrease in tumor coverage was not correlated with the local recurrence probability. The LC and DFS were promising after SBRT of centrally located NSCLC with tumor size, FEV1 and tumor location (for DFS only) as prognostic factors.

Predicting High-Grade Esophagus Toxicity After Treating Central Lung Tumors With Stereotactic Radiation Therapy Using a Normal Tissue Complication Probability Model.

PURPOSE: The treatment of central lung tumors with stereotactic body radiation therapy (SBRT) is challenged by the risk of excessive esophageal toxicity. To improve clinical decision making, we aimed to derive normal tissue complication probability (NTCP) models in a patient cohort with central lung tumors treated with SBRT and to evaluate the currently used esophagus dose constraints. METHODS AND MATERIALS: Patients with a central lung tumor who received SBRT (8 fractions of 7.5 Gy or 12 fractions of 5 Gy) were included. Doses were recalculated to an equivalent dose of 2 Gy with an α/ß-ratio of 10 Gy for acute and 3 Gy for late toxicity (the cut-off was 3 months). The esophagus was manually delineated. NTCP modeling based on logistic regression was used to relate dose-volume histogram parameters (Dmax, D1cc, D2cc, D5cc) to acute and late toxicity. Parameters with a P < .05 were included in the model. Based on the NTCP models, we determined the probability of toxicity for the currently used dose constraints: D1cc ≤40 Gy for 8 fractions and D1cc ≤48 Gy for 12 fractions. RESULTS: For this study, 188 patients with 203 tumors were eligible. Esophagus toxicity occurred in 33 patients (18%). Late high-grade toxicity consisted of 2 possible treatment-related deaths (grade 5) and 2 patients with grade 3 toxicity. Acute toxicity consisted of only grade 1 (n = 19) and grade 2 toxicity (n = 10). All investigated dose-volume histogram parameters were significantly correlated to acute and late toxicity. The probability of late high-grade toxicity is 1.1% for 8 fractions and 1.4% for 12 fractions when applying the current dose constraints. CONCLUSIONS: High-grade esophageal toxicity occurred in 2.1% of the patients, including 2 possible treatment-related deaths. The currently used dose constraints correspond to a low risk of high-grade toxicity.

Lower doses to hippocampi and other brain structures for skull-base meningiomas with intensity modulated proton therapy compared to photon therapy.

BACKGROUND AND PURPOSE: Radiotherapy of skull-base meningiomas is challenging due to the close proximity of multiple sensitive organs at risk (OARs). This study systematically compared intensity modulated proton therapy (IMPT), non-coplanar volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) based on automated treatment planning. Differences in OARs sparing, with specific focus on the hippocampi, and low-dose delivery were quantified. MATERIALS AND METHODS: Twenty patients, target diameter >3 cm, were included. Automated plan generation was used to calculate a VMAT plan with three non-coplanar arcs, an IMRT plan with nine non-coplanar beams with optimized gantry and couch angles, and an IMPT plan with three patient-specific selected non-coplanar beams. A prescription dose of 50.4 GyRBE in 28 fractions was used. The same set of constraints and prioritized objectives was used. All plans were rescaled to the same target coverage. Repeated measures ANOVA was used to assess the statistical significance of differences in OAR dose parameters between planning techniques. RESULTS: Compared to VMAT and IMRT, IMPT significantly improved dose conformity to the target volume. Consequently, large dose reductions in OARs were observed. With respect to VMAT, the mean dose and D40% in the bilateral hippocampus were on average reduced by 48% and 74%, respectively (p ≤ 0.005). With IMPT, the mean dose in the normal brain and volumes receiving 20-30 Gy were up to 47% lower (p ≤ 0.01). When comparing IMPT and IMRT, even larger dose differences in those OARs were observed. CONCLUSION: For skull-base meningiomas IMPT allows for a considerable dose reduction in the hippocampi, normal brain and other OARs compared to both non-coplanar VMAT and IMRT, which may lead to a clinically relevant reduction of late neurocognitive side effects.

Breath-hold versus mid-ventilation in SBRT of adrenal metastases.

PURPOSE: To improve local control in radiotherapy of adrenal metastases precise dose delivery without increasing toxicity is vital. Decreasing the Clinical Target Volume (CTV) - Planning Target Volume (PTV) margins by reducing breathing movement can achieve this. Few data were published concerning the effect of a breath-hold technique. This study investigates the potential of Active Breathing Control (ABC) to limit adrenal breathing movement and reduce CTV-PTV margins. METHODS: We compared adrenal gland movement in free-breathing, making use of the Mid-ventilation (MidV) technique, and with ABC. The coordinates of the adrenal glands obtained on ten phases of a free breathing 4D-CT and on several repeat inspiration ABC CT-scans were measured. Separate coordinates, the random margin component and the margin vector norm were computed and compared between the two techniques. RESULTS: We compared the two techniques in 11 patients (21 adrenal glands) and found the largest movement in the Z-direction, with values of 8.7 ±â€¯4.2 mm for MidV and 2.4 ±â€¯1.5 mm for ABC. In 71% of the cases ABC resulted in a smaller margin component than MidV, although non-significant (p ≥ 0.4). CONCLUSION: Movement of the adrenal gland is largest in the Z-direction. The mean difference in the margin vector norm between both techniques was small with large variations over the patient group, the clinical effect of these differences is unknown. Applying an individualised motion management strategy could be beneficial. If a peak-to-peak amplitude above 15 mm in the Z-direction is observed in the MidV scan we advise to examine if a breath-hold technique could reduce margins.

The influence of a six degrees of freedom couch and an individual head support in patient positioning in radiotherapy of head and neck cancer.

Reproducible patient positioning is important in radiotherapy (RT) of head-and-neck cancer. We therefore compared set-up errors in head-and-neck RT resulting from three different patient positioning systems. Patients were either treated with a standard head support (SHS) and conventional treatment couch (SHS-3, n = 10), a SHS and rotational couch (SHS-6, n = 10), or an individual head support (IHS) and rotational couch (IHS-6, n = 10). Interfraction mean translation vector lenghts were significantly lower for IHS-6 compared to SHS-3 (0.8 ±â€¯0.3 mm vs. 1.4 ±â€¯0.7 mm, P = 0.001). Intrafraction displacement was comparable among cohorts. This study showed that the use of a six degrees of freedom couch combined with an IHS in head-and-neck RT resulted in better interfraction reproducibility.