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.

Advances in radiotherapy and its impact on second primary cancer risk: A multi-center cohort study in prostate cancer patients.

BACKGROUND: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa). METHODS: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT. RESULTS: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints. CONCLUSION: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important.

Corrigendum to "Evaluation of image-guided and surface-guided radiotherapy for breast cancer patients treated in deep inspiration breath-hold: A single institution experience" [Tech. Innov. Patient Support Radiat. Oncol. 21 (2022) 51-57].

[This corrects the article DOI: 10.1016/j.tipsro.2022.02.001.].

Evaluation of image-guided and surface-guided radiotherapy for breast cancer patients treated in deep inspiration breath-hold: A single institution experience.

INTRODUCTION: Nowadays, deep inspiratory breath-hold is a common technique to reduce heart dose in left-sided breast radiotherapy. This study evaluates the evolution of the breath-hold technique in our institute, from portal imaging during dose delivery to continuous monitoring with surface-guided radiotherapy (SGRT). MATERIALS AND METHODS: Setup data and portal imaging results were analyzed for 98 patients treated before 2014, and SGRT data for 228 patients treated between 2018 and 2020. For the pre-SGRT group, systematic and random setup errors were calculated for different correction protocols. Residual errors and reproducibility of breath-holds were evaluated for both groups. The benefit of using SGRT for initial positioning was evaluated for another cohort of 47 patients. RESULTS: Online correction reduced the population mean error from 3.9 mm (no corrections) to 1.4 mm. Despite online setup correction, deviations greater than 3 mm were observed in about 10% and 20% of the treatment beams in ventral-dorsal and cranial-caudal directions, respectively. However, these percentages were much smaller than with offline protocols or no corrections. Mean absolute differences between breath-holds within a fraction were smaller in the SGRT-group (1.69 mm) than in the pre-SGRT-group (2.10 mm), and further improved with addition of visual feedback (1.30 mm). SGRT for positioning did not improve setup accuracy, but slightly reduced the time for imaging and setup correction, allowing completion within 3.5 min for 95% of fractions. CONCLUSION: For accurate radiotherapy breast treatments using deep inspiration breath-hold, daily imaging and correction is required. SGRT provides accurate information on patient positioning during treatment and improves patient compliance with visual feedback.

Impact of Advanced Radiotherapy on Second Primary Cancer Risk in Prostate Cancer Survivors: A Nationwide Cohort Study.

PURPOSE: External Beam Radiotherapy (EBRT) techniques dramatically changed over the years. This may have affected the risk of radiation-induced second primary cancers (SPC), due to increased irradiated low dose volumes and scatter radiation. We investigated whether patterns of SPC after EBRT have changed over the years in prostate cancer (PCa) survivors. MATERIALS AND METHODS: PCa survivors diagnosed between 1990-2014 were selected from the Netherlands Cancer Registry. Patients treated with EBRT were divided in three time periods, representing 2-dimensional Radiotherapy (RT), 3-dimensional conformal RT (3D-CRT), and the advanced RT (AdvRT) era. Standardized incidence ratios (SIR) and absolute excess risks (AER) were calculated to estimate relative and excess absolute SPC risks. Sub-hazard ratios (sHRs) were calculated to compare SPC rates between the EBRT and prostatectomy cohort. SPCs were categorized by subsite and anatomic region. RESULTS: PCa survivors who received EBRT had an increased risk of developing a solid SPC (SIR=1.08; 1.05-1.11), especially in patients aged <70 years (SIR=1.13; 1.09-1.16). Pelvic SPC risks were increased (SIR=1.28; 1.23-1.34), with no obvious differences between the three EBRT eras. Non-pelvic SPC were only significantly increased in the AdvRT era (SIR=1.08; 1.02-1.14), in particular for the 1-5 year follow-up period. Comparing the EBRT cohort to the prostatectomy cohort, again an increased pelvic SPC risk was found for all EBRT periods (sHRs= 1.61, 1.47-1.76). Increased non-pelvic SPC risks were present for all RT eras and highest for the AdvRT period (sHRs=1.17, 1.06-1.29). CONCLUSION: SPC risk in patients with EBRT is increased and remained throughout the different EBRT eras. The risk of developing a SPC outside the pelvic area changed unfavorably in the AdvRT era. Prolonged follow-up is needed to confirm this observation. Whether this is associated with increased irradiated low-dose volumes and scatter, or other changes in clinical EBRT practice, is the subject of further research.

Complementing Prostate SBRT VMAT With a Two-Beam Non-Coplanar IMRT Class Solution to Enhance Rectum and Bladder Sparing With Minimum Increase in Treatment Time.

PURPOSE: Enhance rectum and bladder sparing in prostate SBRT with minimum increase in treatment time by complementing dual-arc coplanar VMAT with a two-beam non-coplanar IMRT class solution (CS). METHODS: For twenty patients, an optimizer for automated multi-criterial planning with integrated beam angle optimization (BAO) was used to generate dual-arc VMAT plans, supplemented with five non-coplanar IMRT beams with individually optimized orientations (VMAT+5). In all plan generations, reduction of high rectum dose had the highest priority after obtaining adequate PTV coverage. A CS with two most preferred directions in VMAT+5 and largest rectum dose reductions compared to dual-arc VMAT was then selected to define VMAT+CS. VMAT+CS was compared with automatically generated i) dual-arc coplanar VMAT plans (VMAT), ii) VMAT+5 plans, and iii) IMRT plans with 30 patient-specific non-coplanar beam orientations (30-NCP). Plans were generated for a 4 x 9.5 Gy fractionation scheme. Differences in PTV doses, healthy tissue sparing, and computation and treatment delivery times were quantified. RESULTS: For equal PTV coverage, VMAT+CS, consisting of dual-arc VMAT supplemented with two fixed, non-coplanar IMRT beams with fixed Gantry/Couch angles of 65°/30° and 295°/-30°, significantly reduced OAR doses and the dose bath, compared to dual-arc VMAT. Mean relative differences in rectum Dmean, D1cc, V40GyEq and V60GyEq were 19.4 ± 10.6%, 4.2 ± 2.7%, 34.9 ± 20.3%, and 39.7 ± 23.2%, respectively (all p<0.001). There was no difference in bladder D1cc, while bladder Dmean reduced by 17.9 ± 11.0% (p<0.001). Also, the clinically evaluated urethra D5%, D10%, and D50% showed small, but statistically significant improvements. All patient VX with X = 2, 5, 10, 20, and 30 Gy were reduced with VMAT+CS, with a maximum relative reduction for V10Gy of 19.0 ± 7.3% (p<0.001). Total delivery times with VMAT+CS only increased by 1.9 ± 0.7 min compared to VMAT (9.1 ± 0.7 min). The dosimetric quality of VMAT+CS plans was equivalent to VMAT+5, while optimization times were reduced by a factor of 25 due to avoidance of individualized BAO. Compared to VMAT+CS, the 30-NCP plans were only favorable in terms of dose bath, at the cost of much enhanced optimization and delivery times. CONCLUSIONS: The proposed two-beam non-coplanar class solution to complement coplanar dual-arc VMAT resulted in substantial plan quality improvements for OARs (especially rectum) and reduced irradiated patient volumes with minor increases in treatment delivery times.

The Risk of Second Primary Cancers in Prostate Cancer Survivors Treated in the Modern Radiotherapy Era.

PURPOSE: Concerns have been raised that modern intensity modulated radiotherapy (IMRT) may be associated with increased second primary cancer risks (SPC) compared to previous three-dimensional conformal radiation techniques (3DCRT), due to increased low dose volumes and more out-of-field ionizing dose to peripheral tissue further away from the target. We assessed the impact of treatment technique on SPC risks in a cohort of prostate cancer (PCa) survivors. MATERIAL AND METHODS: The study cohort comprised 1,561 PCa survivors aged 50-79 years at time of radiotherapy, treated between 2006-2013 (N=707 IMRT, N=854 3DCRT). Treatment details were extracted from radiotherapy systems and merged with longitudinal data of the Netherlands Cancer Registry to identify SPCs. Primary endpoint was the development of a solid SPC (excluding skin cancer) in peripheral anatomical regions, i.e. non-pelvic. Applied latency period was 12 months. SPC rates in the IMRT cohort (total cohort and age subgroups) were compared to 1) the 3DCRT cohort by calculating Sub-Hazard Ratios (sHR) using a competing risk model, and 2) to the general male population by calculating Standardized Incidence Ratios (SIR). Models were adjusted for calendar period and age. RESULTS: Median follow-up was 8.0 years (accumulated 11,664 person-years at-risk) with 159 cases developing ≥1 non-pelvic SPC. For IMRT vs 3DCRT we observed a significantly (p=0.03) increased risk (sHR=1.56, 95% Confidence Interval (CI) 1.03-2.36, corresponding estimated excess absolute risk (EAR) of +7 cases per 10,000 person-years). At explorative analysis, IMRT was in particular associated with increased risks within the subgroup of active smokers (sHR 2.94, p=0.01). Within the age subgroups 50-69 and 70-79 years, the sHR for non-pelvic SPC was 3.27 (p=0.001) and 0.96 (p=0.9), respectively. For pelvic SPC no increase was observed (sHR=0.8, p=0.4). Compared to the general population, IMRT was associated with significantly increased risks for non-pelvic SPC in the 50-69 year age group (SIR=1.90, p<0.05) but not in the 70-79 years group (SIR=1.08). CONCLUSION: IMRT is associated with increased SPC risks for subjects who are relatively young at time of treatment. Additional research on aspects of IMRT that may cause this effect is essential to minimize risks for future patients receiving modern radiotherapy.

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.

First fully automated planning solution for robotic radiosurgery - comparison with automatically planned volumetric arc therapy for prostate cancer.

BACKGROUND: For conventional radiotherapy treatment units, automated planning can significantly improve plan quality. For robotic radiosurgery, systems for automatic generation of clinically deliverable plans do not yet exist. For prostate stereotactic body radiation therapy (SBRT), few studies have systematically compared VMAT with robotic treatment. MATERIAL AND METHODS: The multi-criteria autoplanning optimizer, developed at our institute, was coupled to the commercial treatment planning system of our robotic treatment unit, for fully automated generation of clinically deliverable plans (autoROBOT). The system was then validated by comparing autoROBOT plans with manually generated plans. Next, the autoROBOT system was used for systematic comparisons between autoROBOT plans and VMAT plans, that were also automatically generated (autoVMAT). CTV-PTV margins of 3 mm were used for autoROBOT (clinical routine) and autoVMAT plan generation. For autoVMAT, an extra plan was generated with 5 mm margin (often applied for VMAT). Plans were generated for a 4 × 9.5 Gy fractionation scheme. RESULTS: Compared to manual planning, autoROBOT improved rectum D[Formula: see text] (16%), V[Formula: see text] (75%) and D[Formula: see text] (41%), and bladder D[Formula: see text] (37%) (all p [Formula: see text] .002), with equal PTV coverage. In the autoROBOT and autoVMAT comparison, both with 3 mm margin, rectum doses were lower for autoROBOT by 5% for rectum D[Formula: see text] (p=.002), 33% for V[Formula: see text] (p=.001) and 4% for D[Formula: see text] (p=.05), with comparable PTV coverage and other OAR sparing. With 5 mm margin for VMAT, 18/20 plans had a PTV coverage lower than requested (<95%) and all plans had higher rectum doses than autoROBOT (mean percentage differences of 13% for D[Formula: see text], 69% for V[Formula: see text] and 32% for D[Formula: see text] (all p<.001)). CONCLUSIONS: The first system for fully automated generation of clinically deliverable robotic plans was built. Autoplanning did largely enhance robotic plan quality, compared to manual planning. Using autoplanning for both the robotic system and VMAT, superiority of non-coplanar robotic treatment compared to coplanar VMAT for prostate SBRT was demonstrated.

Late toxicity in the randomized multicenter HYPRO trial for prostate cancer analyzed with automated treatment planning.

PURPOSE/OBJECTIVE: Assess to what extent the use of automated treatment planning would have reduced organ-at-risk dose delivery observed in the randomized HYPRO trial for prostate cancer, and estimate related toxicity reductions. Investigate to what extent improved plan quality for hypofractionation scheme as achieved with automated planning can potentially reduce observed enhanced toxicity for the investigated hypofractionation scheme to levels observed for conventional fractionation scheme. MATERIAL/METHODS: For 725 trial patients, VMAT plans were generated with an algorithm for automated multi-criterial plan generation (autoVMAT). All clinically delivered plans (CLINICAL), generated with commonly applied interactive trial-and-error planning were also available for the investigations. Analyses were based on dose-volume histograms (DVH) and predicted normal tissue complication probabilities (NTCP) for late gastrointestinal (GI) toxicity. RESULTS: Compared to CLINICAL, autoVMAT plans had similar or higher PTV coverage, while large and statistically significant OAR sparing was achieved. Mean doses in the rectum, anus and bladder were reduced by 7.8 ±â€¯4.7 Gy, 7.9 ±â€¯6.0 Gy and 4.2 ±â€¯2.9 Gy, respectively (p < 0.001). NTCPs for late grade ≥2 GI toxicity, rectal bleeding and stool incontinence were reduced from 23.3 ±â€¯9.1% to 19.7 ±â€¯8.9%, from 9.7 ±â€¯2.8% to 8.2 ±â€¯2.8%, and from 16.8 ±â€¯8.5% to 13.1 ±â€¯7.2%, respectively (p < 0.001). Reductions in rectal bleeding NTCP were observed for all published Equivalent Uniform Dose volume parameters, n. AutoVMAT allowed hypofractionation with predicted toxicity similar to conventional fractionation with CLINICAL plans. CONCLUSION: Compared to CLINICAL, autoVMAT had superior plan quality, with meaningful NTCP reductions for both conventional fractionation and hypofractionation schemes. AutoVMAT plans might reduce toxicity for hypofractionation to levels that were clinically observed (and accepted) for conventional fractionation. This may be relevant when considering clinical use of the investigated hypofractionation schedule with relatively high fraction dose (3.4 Gy).

Automated VMAT planning for postoperative adjuvant treatment of advanced gastric cancer.

BACKGROUND: Postoperative/adjuvant radiotherapy of advanced gastric cancer involves a large planning target volume (PTV) with multi-concave shapes which presents a challenge for volumetric modulated arc therapy (VMAT) planning. This study investigates the advantages of automated VMAT planning for this site compared to manual VMAT planning by expert planners. METHODS: For 20 gastric cancer patients in the postoperative/adjuvant setting, dual-arc VMAT plans were generated using fully automated multi-criterial treatment planning (autoVMAT), and compared to manually generated VMAT plans (manVMAT). Both automated and manual plans were created to deliver a median dose of 45 Gy to the PTV using identical planning and segmentation parameters. Plans were evaluated by two expert radiation oncologists for clinical acceptability. AutoVMAT and manVMAT plans were also compared based on dose-volume histogram (DVH) and predicted normal tissue complication probability (NTCP) analysis. RESULTS: Both manVMAT and autoVMAT plans were considered clinically acceptable. Target coverage was similar (manVMAT: 96.6 ± 1.6%, autoVMAT: 97.4 ± 1.0%, p = 0.085). With autoVMAT, median kidney dose was reduced on average by > 25%; (for left kidney from 11.3 ± 2.1 Gy to 8.9 ± 3.5 Gy (p = 0.002); for right kidney from 9.2 ± 2.2 Gy to 6.1 ± 1.3 Gy (p <  0.001)). Median dose to the liver was lower as well (18.8 ± 2.3 Gy vs. 17.1 ± 3.6 Gy, p = 0.048). In addition, Dmax of the spinal cord was significantly reduced (38.3 ± 3.7 Gy vs. 31.6 ± 2.6 Gy, p <  0.001). Substantial improvements in dose conformity and integral dose were achieved with autoVMAT plans (4.2% and 9.1%, respectively; p <  0.001). Due to the better OAR sparing in the autoVMAT plans compared to manVMAT plans, the predicted NTCPs for the left and right kidney and the liver-PTV were significantly reduced by 11.3%, 12.8%, 7%, respectively (p ≤ 0.001). Delivery time and total number of monitor units were increased in autoVMAT plans (from 168 ± 19 s to 207 ± 26 s, p = 0.006) and (from 781 ± 168 MU to 1001 ± 134 MU, p = 0.003), respectively. CONCLUSIONS: For postoperative/adjuvant radiotherapy of advanced gastric cancer, involving a complex target shape, automated VMAT planning is feasible and can substantially reduce the dose to the kidneys and the liver, without compromising the target dose delivery.

A novel method for sub-arc VMAT dose delivery verification based on portal dosimetry with an EPID.

PURPOSE: The EPID-based sub-arc verification of VMAT dose delivery requires synchronization of the acquired electronic portal images (EPIs) with the VMAT delivery, that is, establishment of the start- and stop-MU of the acquired images. To realize this, published synchronization methods propose the use of logging features of the linac or dedicated hardware solutions. In this study, we developed a novel, software-based synchronization method that only uses information inherently available in the acquired images. METHOD: The EPIs are continuously acquired during pretreatment VMAT delivery and converted into Portal Dose Images (PDIs). Sub-arcs of approximately 10 MU are then defined by combining groups of sequentially acquired PDIs. The start- and stop-MUs of measured sub-arcs are established in a synchronization procedure, using only dosimetric information in measured and predicted PDIs. Sub-arc verification of a VMAT dose delivery is based on comparison of measured sub-arc PDIs with synchronized, predicted sub-arc PDIs, using γ-analyses. To assess the accuracy of this new method, measured and predicted PDIs were compared for 20 clinically applied VMAT prostate cancer plans. The sensitivity of the method for detection of delivery errors was investigated using VMAT deliveries with intentionally inserted, small perturbations (25 error scenarios; leaf gap deviations ≤ 1.5 mm, leaf motion stops during ≤ 15 MU, linac output error ≤ 2%). RESULTS: For the 20 plans, the average failed pixel rates (FPR) for full-arc and sub-arc dose QA were 0.36% ± 0.26% (1 SD) and 0.64% ± 0.88%, based on 2%/2 mm and 3%/3 mm γ-analyses, respectively. Small systematic perturbations of up to 1% output error and 1 mm leaf offset were detected using full-arc QA. Sub-arc QA was able to detect positioning errors in three leaves only during approximately 20 MU and small dose delivery errors during approximately 40 MU. In an ROC analysis, the area under the curve (AUC) for the combined full-arc/sub-arc approach was 0.90. CONCLUSIONS: A novel method for sub-arc VMAT dose delivery verification with EPIDs is proposed, using only dosimetric information in acquired EPIs for synchronization. Especially in combination with full-arc QA, the established sensitivity for detection of very small errors is high, with also a high specificity.

VMAT plus a few computer-optimized non-coplanar IMRT beams (VMAT+) tested for liver SBRT.

PURPOSE: To propose a novel treatment approach, designated VMAT+, involving addition of <5 IMRT beams with computer-optimized non-coplanar orientations to VMAT, and evaluate it for liver Stereotactic Body Radiation Therapy (SBRT). VMAT+ is investigated as an alternative for (1) coplanar VMAT and (2) multi-beam non-coplanar treatment. METHODS/MATERIALS: For fifteen patients with liver metastases, VMAT+ plans were compared with (1) dual-arc VMAT and (2) 25-beam, non-coplanar treatment with computer-optimized beam orientations (25-NCP). All plans were generated fully automatically for delivery of the highest feasible tumor Biologically Effective Dose (BED). OAR doses, intermediate-dose-spillage, dose-compactness, and measured delivery times were evaluated. RESULTS: With VMAT+ the maximum achievable tumor BED was equal to that of 25-NCP. Conversely, VMAT resulted in a lower tumor BED in 5 patients. Compared to VMAT, VMAT+ yielded significant dose reductions in OARs. Intermediate-dose-spillage and dose-compactness were significantly improved by 9.8% and 17.3% (p≤0.002), respectively. Treatment times with VMAT+ were only enhanced by 4.1min on average, compared to VMAT (8.4min). Improvements in OAR sparing with 25-NCP, compared to VMAT+, were generally modest and/or statistically insignificant, while delivery times were on average 20.5min longer. CONCLUSIONS: For liver SBRT, VMAT+ is equivalent to time-consuming treatment with 25 non-coplanar beams in terms of achievable tumor BED. Compared to VMAT, OAR sparing and intermediate-dose-spillage are significantly improved, with minor increase in delivery time.

Fully automated VMAT treatment planning for advanced-stage NSCLC patients.

PURPOSE: To develop a fully automated procedure for multicriterial volumetric modulated arc therapy (VMAT) treatment planning (autoVMAT) for stage III/IV non-small cell lung cancer (NSCLC) patients treated with curative intent. MATERIALS AND METHODS: After configuring the developed autoVMAT system for NSCLC, autoVMAT plans were compared with manually generated clinically delivered intensity-modulated radiotherapy (IMRT) plans for 41 patients. AutoVMAT plans were also compared to manually generated VMAT plans in the absence of time pressure. For 16 patients with reduced planning target volume (PTV) dose prescription in the clinical IMRT plan (to avoid violation of organs at risk tolerances), the potential for dose escalation with autoVMAT was explored. RESULTS: Two physicians evaluated 35/41 autoVMAT plans (85%) as clinically acceptable. Compared to the manually generated IMRT plans, autoVMAT plans showed statistically significant improved PTV coverage (V95% increased by 1.1% ± 1.1%), higher dose conformity (R50 reduced by 12.2% ± 12.7%), and reduced mean lung, heart, and esophagus doses (reductions of 0.9 Gy ± 1.0 Gy, 1.5 Gy ± 1.8 Gy, 3.6 Gy ± 2.8 Gy, respectively, all p < 0.001). To render the six remaining autoVMAT plans clinically acceptable, a dosimetrist needed less than 10 min hands-on time for fine-tuning. AutoVMAT plans were also considered equivalent or better than manually optimized VMAT plans. For 6/16 patients, autoVMAT allowed tumor dose escalation of 5-10 Gy. CONCLUSION: Clinically deliverable, high-quality autoVMAT plans can be generated fully automatically for the vast majority of advanced-stage NSCLC patients. For a subset of patients, autoVMAT allowed for tumor dose escalation.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial.

BACKGROUND: In 2007, we began the randomised phase 3 multicentre HYPRO trial to investigate the effect of hypofractionated radiotherapy compared with conventionally fractionated radiotherapy on relapse-free survival in patients with prostate cancer. Here, we examine whether patients experience differences in acute gastrointestinal and genitourinary adverse effects. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a PSA concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with minimisation procedure, stratified by treatment centre and risk group. The primary endpoint is 5-year relapse-free survival. Here we report data for the acute toxicity outcomes: the cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. Non-inferiority of hypofractionation was tested separately for genitourinary and gastrointestinal acute toxic effects, with a null hypothesis that cumulative incidences of each type of adverse event were not more than 8% higher in the hypofractionation group than in the standard fractionation group. We scored acute genitourinary and gastrointestinal toxic effects according to RTOG-EORTC criteria from both case report forms and patients' self-assessment questionnaires, at baseline, twice during radiotherapy, and 3 months after completion of radiotherapy. Analyses were done in the intention-to-treat population. Patient recruitment has been completed. This study is registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were randomly assigned to treatment with standard fractionation (n=410) or hypofractionation (n=410). 3 months after radiotherapy, 73 (22%) patients in the standard fractionation group and 75 (23%) patients in the hypofractionation group reported grade 2 or worse genitourinary toxicity; grade 2 or worse gastrointestinal toxicity was noted in 43 (13%) patients in the standard fractionation group and in 42 (13%) in the hypofractionation group. Grade 4 acute genitourinary toxicity was reported for two patients, one (<1%) in each group. No grade 4 acute gastrointestinal toxicities were observed. We noted no significant difference in cumulative incidence by 120 days after radiotherapy of grade 2 or worse acute genitourinary toxicity (57·8% [95% CI 52·9-62·7] in the standard fractionation group vs 60·5% (55·8-65·3) in the hypofractionation group; difference 2·7%, 90% CI -2·99 to 8·48; odds ratio [OR] 1·12, 95% CI 0·84-1·49; p=0·43). The cumulative incidence of grade 2 or worse acute gastrointestinal toxicity by 120 days after radiotherapy was higher in patients given hypofractionation (31·2% [95% CI 26·6-35·8] in the standard fractionation group vs 42·0% [37·2-46·9] in the hypofractionation group; difference 10·8%, 90% CI 5·25-16·43; OR 1·6; p=0·0015; non-inferiority not confirmed). INTERPRETATION: Hypofractionated radiotherapy was not non-inferior to standard fractionated radiotherapy in terms of acute genitourinary and gastrointestinal toxicity for men with intermediate-risk and high-risk prostate cancer. In fact, the cumulative incidence of grade 2 or worse acute gastrointestinal toxicity was significantly higher in patients given hypofractionation than in those given standard fractionated radiotherapy. Patients remain in follow-up for efficacy endpoints. FUNDING: The Dutch Cancer Society.

Fully automated volumetric modulated arc therapy plan generation for prostate cancer patients.

PURPOSE: To develop and evaluate fully automated volumetric modulated arc therapy (VMAT) treatment planning for prostate cancer patients, avoiding manual trial-and-error tweaking of plan parameters by dosimetrists. METHODS AND MATERIALS: A system was developed for fully automated generation of VMAT plans with our commercial clinical treatment planning system (TPS), linked to the in-house developed Erasmus-iCycle multicriterial optimizer for preoptimization. For 30 randomly selected patients, automatically generated VMAT plans (VMATauto) were compared with VMAT plans generated manually by 1 expert dosimetrist in the absence of time pressure (VMATman). For all treatment plans, planning target volume (PTV) coverage and sparing of organs-at-risk were quantified. RESULTS: All generated plans were clinically acceptable and had similar PTV coverage (V95% > 99%). For VMATauto and VMATman plans, the organ-at-risk sparing was similar as well, although only the former plans were generated without any planning workload. CONCLUSIONS: Fully automated generation of high-quality VMAT plans for prostate cancer patients is feasible and has recently been implemented in our clinic.

Accurate IMRT fluence verification for prostate cancer patients using 'in-vivo' measured EPID images and in-room acquired kilovoltage cone-beam CT scans.

BACKGROUND: To investigate for prostate cancer patients the comparison of 'in-vivo' measured portal dose images (PDIs) with predictions based on a kilovoltage cone-beam CT scan (CBCT), acquired during the same treatment fraction, as an alternative for pre-treatment verification. For evaluation purposes, predictions were also performed using the patients' planning CTs (pCT). METHODS: To get reliable CBCT electron densities for PDI predictions, Hounsfield units from the pCT were mapped onto the CBCT, while accounting for non-rigidity in patient anatomy in an approximate way. PDI prediction accuracy was first validated for an anatomical phantom, using IMRT treatment plans of ten prostate cancer patients. Clinical performance was studied using data acquired for 50 prostate cancer patients. For each patient, 4-5 CBCTs were available, resulting in a total of 1413 evaluated images. Measured and predicted PDIs were compared using γ-analyses with 3% global dose difference and 3 mm distance to agreement as reference criteria. Moreover, the pass rate for automated PDI comparison was assessed. To quantify improvements in IMRT fluence verification accuracy results from multiple fractions were combined by generating a γ-image with values halfway the minimum and median γ values, pixel by pixel. RESULTS: For patients, CBCT-based PDI predictions showed a high agreement with measurements, with an average percentage of rejected pixels of 1.41% only. In spite of possible intra-fraction motion and anatomy changes, this was only slightly larger than for phantom measurements (0.86%). For pCT-based predictions, the agreement deteriorated (average percentage of rejected pixels 2.98%), due to an enhanced impact of anatomy variations. For predictions based on CBCT, combination of the first 2 fractions yielded gamma results in close agreement with pre-treatment analyses (average percentage of rejected pixels 0.63% versus 0.35%, percentage of rejected beams 0.6% versus 0%). For the pCT-based approach, only combination of the first 5 fractions resulted in acceptable agreement with pre-treatment results. CONCLUSION: In-room acquired CBCT scans can be used for high accuracy IMRT fluence verification based on in-vivo measured EPID images. Combination of γ results for the first 2 fractions can largely compensate for small accuracy reductions, with respect to pre-treatment verification, related to intra-fraction motion and anatomy changes.

Automated generation of IMRT treatment plans for prostate cancer patients with metal hip prostheses: comparison of different planning strategies.

PURPOSE: To compare IMRT planning strategies for prostate cancer patients with metal hip prostheses. METHODS: All plans were generated fully automatically (i.e., no human trial-and-error interactions) using iCycle, the authors' in-house developed algorithm for multicriterial selection of beam angles and optimization of fluence profiles, allowing objective comparison of planning strategies. For 18 prostate cancer patients (eight with bilateral hip prostheses, ten with a right-sided unilateral prosthesis), two planning strategies were evaluated: (i) full exclusion of beams containing beamlets that would deliver dose to the target after passing a prosthesis (IMRT remove) and (ii) exclusion of those beamlets only (IMRT cut). Plans with optimized coplanar and noncoplanar beam arrangements were generated. Differences in PTV coverage and sparing of organs at risk (OARs) were quantified. The impact of beam number on plan quality was evaluated. RESULTS: Especially for patients with bilateral hip prostheses, IMRT cut significantly improved rectum and bladder sparing compared to IMRT remove. For 9-beam coplanar plans, rectum V60 Gy reduced by 17.5% ± 15.0% (maximum 37.4%, p = 0.036) and rectum D mean by 9.4% ± 7.8% (maximum 19.8%, p = 0.036). Further improvements in OAR sparing were achievable by using noncoplanar beam setups, reducing rectum V 60Gy by another 4.6% ± 4.9% (p = 0.012) for noncoplanar 9-beam IMRT cut plans. Large reductions in rectum dose delivery were also observed when increasing the number of beam directions in the plans. For bilateral implants, the rectum V 60Gy was 37.3% ± 12.1% for coplanar 7-beam plans and reduced on average by 13.5% (maximum 30.1%, p = 0.012) for 15 directions. CONCLUSIONS: iCycle was able to automatically generate high quality plans for prostate cancer patients with prostheses. Excluding only beamlets that passed through the prostheses (IMRTcut strategy) significantly improved OAR sparing. Noncoplanar beam arrangements and, to a larger extent, increasing the number of treatment beams further improved plan quality.

Toward fully automated multicriterial plan generation: a prospective clinical study.

PURPOSE: To prospectively compare plans generated with iCycle, an in-house-developed algorithm for fully automated multicriterial intensity modulated radiation therapy (IMRT) beam profile and beam orientation optimization, with plans manually generated by dosimetrists using the clinical treatment planning system. METHODS AND MATERIALS: For 20 randomly selected head-and-neck cancer patients with various tumor locations (of whom 13 received sequential boost treatments), we offered the treating physician the choice between an automatically generated iCycle plan and a manually optimized plan using standard clinical procedures. Although iCycle used a fixed "wish list" with hard constraints and prioritized objectives, the dosimetrists manually selected the beam configuration and fine tuned the constraints and objectives for each IMRT plan. Dosimetrists were not informed in advance whether a competing iCycle plan was made. The 2 plans were simultaneously presented to the physician, who then selected the plan to be used for treatment. For the patient group, differences in planning target volume coverage and sparing of critical tissues were quantified. RESULTS: In 32 of 33 plan comparisons, the physician selected the iCycle plan for treatment. This highly consistent preference for the automatically generated plans was mainly caused by the improved sparing for the large majority of critical structures. With iCycle, the normal tissue complication probabilities for the parotid and submandibular glands were reduced by 2.4% ± 4.9% (maximum, 18.5%, P=.001) and 6.5% ± 8.3% (maximum, 27%, P=.005), respectively. The reduction in the mean oral cavity dose was 2.8 ± 2.8 Gy (maximum, 8.1 Gy, P=.005). For the swallowing muscles, the esophagus and larynx, the mean dose reduction was 3.3 ± 1.1 Gy (maximum, 9.2 Gy, P<.001). For 15 of the 20 patients, target coverage was also improved. CONCLUSIONS: In 97% of cases, automatically generated plans were selected for treatment because of the superior quality. Apart from the improved plan quality, automatic plan generation is economically attractive because of the reduced workload.

Integrated multicriterial optimization of beam angles and intensity profiles for coplanar and noncoplanar head and neck IMRT and implications for VMAT.

PURPOSE: To quantify improved salivary gland sparing for head and neck cancer patients using intensity-modulated radiotherapy (IMRT) plans based on integrated computerized optimization of beam orientations and intensity profiles. To assess if optimized nonzero couch angles also improve VMAT plans. METHODS: Our in-house developed algorithm iCycle was used for automated generation of multicriterial optimized plans with optimized beam orientations and intensity profiles, and plans with optimized profiles for preselected beam arrangements. For 20 patients, five IMRT plans, based on one "wish-list," were compared: (i) and (ii) seven- and nine-beam equiangular coplanar plans (iCycle(7equi), iCycle(9equi)), (iii) and (iv) nine-beam plans with optimized coplanar and noncoplanar beam orientations (iCycle(copl), iCycle(noncopl)), and (v) a nine-beam coplanar plan with optimized gantry angles and one optimized couch rotation (iCycle(couch)). VMAT plans without and with this optimized couch rotation were evaluated. RESULTS: iCycle(noncopl) resulted in the best salivary gland sparing, while iCycle(couch) yielded similar results for 18 patients. For iCycle(7equi), submandibular gland NTCP values were on average 5% higher. iCycle(9equi) performed better than iCycle(7equi). iCycle(copl) showed further improvement. Application of the optimized couch angle from iCycle(couch) also improved NTCP values in VMAT plans. CONCLUSIONS: iCycle allows objective comparison of competing planning strategies. Integrated optimization of beam profiles and angles can significantly improve normal tissue sparing, yielding optimal results for iCycle(noncopl).