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Purpose: To investigate the interobserver variability (IOV) in target volume delineation of definitive radiotherapy for thoracic esophageal cancer (TEC) among cancer centers in China, and ultimately improve contouring consistency as much as possible to lay the foundation for multi-center prospective studies., Methods: Sixteen cancer centers throughout China participated in this study. In Phase 1, three suitable cases with upper, middle, and lower TEC were chosen, and participants were asked to contour a group of gross tumor volume (GTV-T), nodal gross tumor volume (GTV-N) and clinical target volume (CTV) for each case based on their routine experience. In Phase 2, the same clinicians were instructed to follow a contouring protocol to re-contour another group of target volume. The variation of the target volume was analyzed and quantified using dice similarity coefficient (DSC)., Results: Sixteen clinicians provided routine volumes, whereas ten provided both routine and protocol volumes for each case. The IOV of routine GTV-N was the most striking in all cases, with the smallest DSC of 0.37 (95% CI 0.32-0.42), followed by CTV, whereas GTV-T showed high consistency. After following the protocol, the smallest DSC of GTV-N was improved to 0.64 (95% CI 0.45-0.83, P = 0.005) but the DSC of GTV-T and CTV remained constant in most cases., Conclusion: Variability in target volume delineation was observed, but it could be significantly reduced and controlled using mandatory interventions.

Background: The optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC., Methods: This multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED 10  ≥ 100 Gy), SbRT (EQD 2  > 74 Gy to BED 10  < 100 Gy), and ScRT (EQD 2  < 74 Gy). Overall survival (OS), progression-free survival (PFS), local control (LC), and intrahepatic control (IC) were evaluated in univariable and multivariable analyses., Results: The median tumor size was 5.6 cm (interquartile range [IQR] 1.1-21.0 cm). The median follow-up time was 50.0 months (IQR 6-100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control., Conclusions: If tolerated by normal tissue, we recommend SaRT (BED 10  ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD 2  ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD 2  < 74 Gy) is recommended as palliative irradiation.

Background: Segmentation is a crucial step in treatment planning that directly impacts dose distribution and optimization. The aim of this study was to evaluate the inter-individual variability of common cranial organs at risk (OAR) delineation in neurooncology practice., Methods: Anonymized simulation contrast-enhanced CT and MR scans of one patient with a solitary brain metastasis was used for delineation and analysis. Expert professionals from 16 radiotherapy centers involved in brain structures delineation were asked to segment 9 OAR on their own treatment planning system. As reference, two experts in neurooncology, produced a unique consensual contour set according to guidelines. Overlap ratio, Kappa index (KI), volumetric ratio, Commonly Contoured Volume, Supplementary Contoured Volume were evaluated using Artiview™ v 2.8.2-according to occupation, seniority and level of expertise of all participants., Results: For the most frequently delineated and largest OAR, the mean KI are often good (0.8 for the parotid and the brainstem); however, for the smaller OAR, KI degrade (0.3 for the optic chiasm, 0.5% for the cochlea), with a significant discrimination (p < 0.01). The radiation oncologists, members of Association des Neuro-Oncologue d'Expression Française society performed better in all indicators compared to non-members (p < 0.01). Our exercise was effective in separating the different participating centers with 3 of the reported indicators (p < 0.01)., Conclusion: Our study illustrates the heterogeneity in normal structures contouring between professionals. We emphasize the need for cerebral OAR delineation harmonization-that is a major determinant of therapeutic ratio and clinical trials evaluation.

Background: Conservative surgery followed by breast and nodal irradiation is the standard loco-regional early breast cancer (BC) treatment for patients with four or more involved lymph nodes. However, the treatment strategy when fewer nodes are involved remains unclear, especially when lymphadenectomy has not been performed. Sensitive nodal status assessment molecular techniques as the One-Step Nucleic Acid Amplification (OSNA) assay can contribute to the definition and standardization of the treatment strategy. Therefore, the OPTIMAL study aims to demonstrate the feasibility of incidental irradiation of axillary nodes in patients with early-stage BC and limited involvement of the SLN., Methods: BC patients who underwent conservative surgery and whose SLN total tumour load assessed with OSNA ranged between 250-15,000 copies/µL will be eligible. Patients will be randomized to receive irradiation on the breast, tumour bed, axillary and supraclavicular lymph node areas (intentional arm) or only on the breast and tumour bed (incidental arm). All areas, including the internal mammary chain, will be contoured. The mean, median, D5% and D95% doses received in all volumes will be calculated. The primary endpoint is the non-inferiority of the incidental irradiation of axillary nodes compared to the intentional irradiation in terms of 5-year disease free survival. Secondary endpoints comprise the comparison of acute and chronic toxicity and loco-regional and distant disease recurrence rates., Discussion: Standardizing the treatment and diagnosis of BC patients with few nodes affected is crucial due to the lack of consensus. Hence, the quantitative score for the metastatic burden of SLN provided by OSNA can contribute by improving the discrimination of which BC patients with limited nodal involvement can benefit from incidental radiation as an adjuvant treatment strategy., Trial Registration: ClinicalTrial.gov, NCT02335957; https://clinicaltrials.gov/ct2/show/NCT02335957.

Background: Online adaptive radiotherapy is intended to prevent plan degradation caused by inter-fractional tumor volume and shape changes, but time limitations make online re-planning challenging. The aim of this study was to compare the quality of online-adapted plans to their respective reference treatment plans., Methods: Fifty-two patients treated on a ViewRay MRIdian Linac were included in this retrospective study. In total 238 online-adapted plans were analyzed, which were optimized with either changing of the segment weights (n = 85) or full re-optimization (n = 153). Five different treatment sites were evaluated: prostate, abdomen, liver, lung and pelvis. Dosimetric parameters of gross tumor volume (GTV), planning target volume (PTV), 2 cm ring around the PTV and organs at risk (OARs) were considered. The Wilcoxon signed-rank test was used to assess differences between online-adapted and reference treatment plans, p < 0.05 was considered significant., Results: The average duration of the online adaptation, consisting of contour editing, plan optimization and quality assurance (QA), was 24 ± 6 min. The GTV was slightly larger (average ± SD: 1.9% ± 9.0%) in the adapted plans than in the reference plans (p < 0.001). GTV-D 95% exhibited no significant changes when considering all plans, but GTV-D 2% increased by 0.40% ± 1.5% on average (p < 0.001). There was a very small yet significant decrease in GTV-coverage for the abdomen plans. The ring D mean increased on average by 1.0% ± 3.6% considering all plans (p < 0.001). There was a significant reduction of the dose to the rectum of 4.7% ± 16% on average (p < 0.001) for prostate plans., Conclusions: Dosimetric quality of online-adapted plans was comparable to reference treatment plans and OAR dose was either comparable or decreased, depending on treatment site. However, dose spillage was slightly increased.

Background: To quantify the dosimetric parameters of different bone marrow sparing strategies and to determine the optimal strategy for cervical cancer patients undergoing postoperative intensity-modulated radiotherapy (IMRT)., Methods: Fifteen patients with cervical cancer were selected for analysis. The planning target volume (PTV) and the organs at risks (OAR) including small bowel, bladder, rectum, femoral heads, os coxae (OC), lumbosacral spine (LS) and bone marrow (BM) were contoured. For each patient, four IMRT plans with different strategies were generated, including one plan without BM as the dose-volume constraint, namely IMRT (N) plan, and three bone marrow sparing (BMS-IMRT) plans. The three BMS-IMRT plans used the BM, OC, OC and LS respectively, as the BM OAR, namely as IMRT (BM), IMRT (OC) and IMRT (OC + LS) plans. Dose volumes for the target and the OARs were compared using analysis of variance (ANOVA)., Results: Compared with IMRT (N) plans, the dose to the small bowel, bladder, rectum and femoral heads showed no increase in the three BMS-IMRT plans. However, the irradiated dose to BM, OC and LS significantly decreased. In particular, the mean dose of BM, OC and LS decreased by about 5Gy (p < 0.05) in IMRT (BM) plans while the average volume receiving ≥20, ≥30, ≥40Gy decreased by 7.1-24.2%. The LS volume receiving 40Gy showed the highest decrease (about 31.2%, p < 0.05) in IMRT (OC + LS) plans. On the other hand, in comparison with IMRT (BM), IMRT (OC) reduced the dose volume of to the OC, but increased the dose to LS while IMRT (OC + LS) plans reduced both the OC and the LS volume at all dose levels. Specifically, the V 20 of OC and LS in the IMRT (OC + LS) plan decreased by 11.5 and 11.2%, respectively., Conclusion: By introducing the os coxae and lumbosacral spine as the dose-volume constraints, the IMRT plans exhibited the best sparing of the bone marrow without compromising the dose to surrounding normal structures. Therefore, we recommend adding the os coxae and lumbosacral spine as the BM OAR in such plans.

Background: The purpose of this study was to assess compliance with treatment planning in a dummy-run for a multicenter clinical trial involving patients with high-risk postoperative uterine cervical cancer using intensity-modulated radiation therapy (IMRT) (JCOG1402 trial)., Methods: For the dummy-run, we prepared a computed tomography dataset comprising two anonymized cases of post-hysterectomy cervical cancer. These were sent to the 47 participating institutions to assess institutional plan quality such as delineations and dose distributions., Results: Central review showed 3 and 4 deviations per treatment plan on average. The deviations related to the nodal and vaginal cuff clinical target volume (CTV) delineation, which accounted for approximately 50% of the total deviations. The CTV vaginal cuff showed considerable differences in delineation compared with the nodal CTV. For the Dice similarity coefficient, case 1 showed a mean ± 1σ of 0.81 ± 0.03 and 0.60 ± 0.09 for the nodal and the CTV vaginal cuff, respectively, while these were 0.81 ± 0.04 and 0.54 ± 0.14, respectively, for case two. Of the 47 institutions, 10 were required to resubmit their treatment plan because the delineations, planning target volume margin, and required dose distributions were not in accordance with the JCOG1402 protocol., Conclusions: The dummy-run test in postoperative uterine cervical cancer demonstrated substantial deviations in the delineations, particularly for the CTV vaginal cuff. The analysis data could provide helpful information on delineation and planning, allowing standardization of IMRT planning for postoperative uterine cervical cancer., Trial Registration: Japanese Clinical Trial Registry #: UMIN000027017 at https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000030672;language=J.

Purpose: To assess the worst-case robust optimization IMPT plans with setup and range uncertainties and to test the hypothesis that the worst-case robust optimization strategies could cover most possible setup and range uncertainties in the real scenarios., Methods: We analyzed the nominal and worst-case robust optimization IMPT plans of seven patients with head and neck cancer patients. To take uncertainties into account for the dose calculation, we performed a comprehensive simulation in which the dose was recalculated 625 times per given plan using Gaussian systematic setup and proton range uncertainties. Subsequently, based on the simulation results, we calculated the target coverage in all perturbation scenarios, as well as the ratios of target coverage located within the threshold of eight worst-case scenarios. We set the criteria for the optimized plan to be the ratios of 1) the dose delivered to 95% (D95%) of clinical target volumes 1 and 2 (CTV1 and CTV2) above 95% of the prescribed dose, and 2) the D95% of clinical target volume 3 (CTV3) above 90% of the prescribed dose in worst-case situations., Results: The probability that the perturbed-dose indices of the CTVs in each scenario were within the worst-case scenario limits ranged from 89.51 to 91.22% for both the nominal and worst-case robust optimization IMPT plans. A quartile analysis showed that the selective robust optimization IMPT plans all had higher D95% values for CTV1, CTV2, and CTV3 than did the nominal IMPT plans., Conclusions: The worst-case strategy for robust optimization is adequately models and covers most of the setup and range uncertainties for the IMPT treatment of head and neck patients in our center.

Background: To analyze and present the China's national survey on patient-specific IMRT quality assurance (QA)., Methods: A national survey was conducted in all radiotherapy centers in China to collect comprehensive information on status of IMRT QA practice, including machine, technique, equipment, issues and suggestions., Results: Four hundred and three centers responded to this survey, accounting for 56.92% of all the centers implementing IMRT in China. The total number of medical physicists and the total number of patients treated with IMRT annually in these centers was 1599 and 305,000 respectively. All centers implemented measurement-based verification. Point dose verification and 2D dose verification was implemented in 331 and 399 centers, respectively. Three hundred forty-eight centers had 2D arrays, and 52 centers had detector devices designed to measure VMAT beams. EPID and film were used in 78 and 70 centers, respectively. Seventeen and 20 centers used log file and 3D DVH analysis, respectively. One hundred sixty-eight centers performed measurement-based verification not for each patient based on different selection criteria. The techniques and methods varied significantly in both point dose and dose distribution verification, from evaluation metrics, criteria, tolerance limit, and steps to check failed IMRT QA plans. Major issues identified in this survey were the limited resources of physicists, QA devices, and linacs., Conclusions: IMRT QA was implemented in all the surveyed centers. The practice of IMRT QA varied significantly between centers. An increase in personnel, QA devices and linacs is highly desired. National standard, guideline, regulation and training programs are urgently needed in China for consistent and effective implementation of IMRT QA.

Background: To evaluate the modulation indices (MIs) for predicting the plan delivery accuracies of intensity-modulated radiation therapy (IMRT) plans., Methods: A total of 100 dynamic IMRT plans that used TrueBeam STx and 102 dynamic IMRT plans that used Trilogy were selected. For each plan, various MIs were calculated, which included the modulation complexity score (MCS), plan-averaged beam area (PA), plan-averaged beam irregularity (PI), plan-averaged beam modulation (PM), MI quantifying multi-leaf collimator (MLC) speeds (MI s ), MI quantifying MLC acceleration (MI a ), and MI quantifying MLC acceleration and segment aperture irregularity (MI c,IMRT ). To determine plan delivery accuracy, global gamma passing rates, MLC errors of log files, and dose-volumetric parameter differences between original and log file-reconstructed IMRT plans were obtained. To assess the ability of each MI for predicting plan delivery accuracy, Spearman's rank correlation coefficients (r s ) between MIs and plan delivery accuracy measures were calculated., Results: PI showed moderately strong correlations with gamma passing rates in MapCHECK2 measurements of both TrueBeam STx and Trilogy (r s  = - 0.591 with p <  0.001 and - 0.427 with p <  0.001 to with gamma criterion of 2%/2 mm, respectively). For ArcCHECK measurements, PI also showed moderately strong correlations with the gamma passing rates in the ArcCHECK measurements of TrueBeam STx and Trilogy (r s  = - 0.545 with p <  0.001 and r s  = - 0.581 with p <  0.001 with gamma criterion of 2%/2 mm, respectively). The PI showed the second strongest correlation with MLC errors in both TrueBeam STx and Trilogy (r s  = 0.861 with p <  0.001 and r s  = 0.767 with p <  0.001, respectively). In general, the PI showed moderately strong correlations with every plan delivery accuracy measure., Conclusions: The PI showed moderately strong correlations with every plan delivery accuracy measure and therefore is a useful predictor of IMRT delivery accuracy.

Background: Automatic multi-criteria optimization is necessary for intensity modulated radiation therapy (IMRT) because of low planning efficiency and large plan quality uncertainty in current clinical practice. Most studies focused on imitating dosimetrists' planning procedures to automate this process and ignored the fact that organ-based objective functions typically used in commercial treatment planning systems (such as dose-volume function) usually lead to sub-optimal plans. To guarantee the optimum results and to automate this process, we incorporate an improved automation strategy and a voxel-based optimization algorithm to generate a novel automatic multi-criteria optimization framework. We then evaluate it in clinical cases., Methods: This novel automatic multi-criteria optimization framework incorporates a ranked priority-list based automatic constraints adjustment strategy and an in-house developed voxel-based optimization algorithm. Constraints are sequentially adjusted following a pre-defined priority list. Afterward, a voxel-based fluence map optimization (FMO) with an orientation to the newly updated constraints is launched to find a Pareto optimal solution. Loops of constraints adjustment are repeated until each of them could not be relaxed or tightened. The feasibility of the framework is evaluated with 10 automatic generated gynecology (GYN) cancer IMRT cases by comparing the dosimetric performance with the original., Results: Plan quality improvement is observed for our automatic multi-criteria optimization method. Comparable DVHs are found for the planning target volume (PTV), but with better organs-at-risk (OAR) dose sparing. Among 13 evaluated dosimetric endpoints, 5 of them show significant improvements in automatically generated plans compared with the original plans. Investigation of improvement tendency during optimization exhibits gradual change as the optimization stage proceeds. An initial voxel-based optimization stage and in-low-priority dosimetric criteria tighten can significantly contribute to the optimization procedure., Conclusions: We have successfully developed an automatic multi-criteria optimization framework that can dramatically reduce the current trial-and-error patterned planning workload while affording an efficient method to assure high plan quality consistency. This optimization framework is expected to greatly facilitate precise radiation therapy because of its advantages of planning efficiency and plan quality improvement.

Background: Melanoma brain metastases (MBM) often cause morbidity and mortality for stage IV melanoma patients. An ongoing randomised phase III trial (NCT01503827 - WBRT-Mel) evaluates the role of adjuvant whole brain radiotherapy (WBRT) following local treatment of MBM. Hippocampal avoidance during WBRT (HA-WBRT) has shown memory and neurocognitive function (NCF) preservation in the RTOG-0933 phase II study. This study assessed the quality assurance of HA-WBRT within the WBRT-Mel trial according to RTOG-0933 study criteria., Methods: Hippocampal avoidance was allowed in approved centres with intensity-modulated radiotherapy capability. Patients treated by HA-WBRT were not randomized within the WBRT arm. The RTOG 0933 contouring Atlas was used to contour hippocampi. In the trial co-ordinating centre, patients were treated with volumetric modulated arc therapy using complementary arcs; similar techniques were used at other sites. Dosimetric data were extracted retrospectively and analysed in accordance with RTOG 0933 study constraints criteria., Results: Among the 215 patients accrued to the WBRT-Mel study between April 2009 and September 2017, 107 were randomized to the WBRT arm, 22 were treated by HA-WBRT in 4 centers. Eighteen patients were treated in the same centre. The median age was 65 years. The commonest (91%) HA-WBRT schema was 30 Gy in 10 fractions. Prior to HA-WBRT, 10 patients had been treated by surgery alone, six by radiosurgery alone, four by surgery and radiosurgery and two exclusively by simultaneous integrated boost concurrent to HA-WBRT. Twenty patients were treated with intention to spare both hippocampi and two patients had MBM close to one hippocampus and were treated with intention to spare the contralateral hippocampus. According to RTOG-0933 study criteria, 18 patients (82%) were treated within constraints and four patients (18%) had unacceptable deviation in just one hippocampus., Conclusions: This dosimetric quality assurance study shows good compliance (82%) according to RTOG-0933 study dosimetric constraints. Indeed, all patients respected RTOG hippocampal avoidance constraints on at least one hippocampus. In the futureanalysis of the WBRT-Mel trial, the NCF of patients on the observation arm, WBRT arm and with HA-WBRT arm will be compared.

Background: In intensity modulated radiation therapy (IMRT) quality assurance (QA), evaluation of QA result using a pass/non-pass strategy under an acceptance criterion often suffers from lack of information on how good the plan is in absolute manner. In this study, we suggested adding an index system, previously developed for dose painting technique, to current IMRT QA process for better understanding of QA result., Methods: The index system consists of three indices, index of achievement (IOA), index of hotness (IOH) and index of coldness (IOC). As indicated by its name, IOA does measure the level of agreement. IOH and IOC, on the other hand, measure the magnitude of overdose and underdose, respectively. A systematic analysis was performed with three 1-dimensional hypothetical dose distributions to investigate the characteristics of the index system. The feasibility of the system was also assessed with clinical volumetric modulated arc therapy (VMAT) QA cases from 8 head & neck and 5 prostate patients. In both simulation studies, certain amount of errors was intentionally induced to each dose distribution. Furthermore, we applied the proposed system to compare calculated with actual measured data for a total of 60 patients (30 head & neck and 30 prostate cases). QA analysis was made using both the index system and gamma method, and results were compared., Results: While the gamma evaluation showed limited sensitivity in evaluating QA result depending on the level of tolerance criteria used, the proposed indices tended to better distinguish plans in terms of the amount of errors. Hotness and coldness of prescribed dose in the plan could be evaluated quantitatively by the indices., Conclusions: The proposed index system provides information with which IMRT QA result would be better evaluated, especially when gamma pass rates are identical or similar among multiple plans. In addition, the independency of the index system on acceptance criteria would help making clear communications among readers of published articles and researchers in multi-institutional studies.

Background: We hypothesized that hippocampal-sparing radiotherapy via volumetric modulated arc therapy (VMAT) could preserve the neurocognitive function (NCF) of patients with primary brain tumors treated with radiotherapy., Methods: We reviewed data from patients with primary brain tumors who underwent hippocampal-sparing brain radiotherapy via VMAT between February 2014 and December 2015. The optimization criteria for the contralateral hippocampus was a maximum dose (D max ) of less than 17 Gy. For NCF evaluations, the Seoul Verbal Learning Test for total recall, delayed recall, and recognition (SVLT-TR, DR, and Recognition) was performed at baseline and at seven months after radiotherapy., Results: A total of 26 patients underwent NCF testing seven months after radiotherapy. Their median age was 49.5 years (range 26-77 years), and 14 (53.8%) had grade III/IV tumors. The median D max to the contralateral hippocampus was 16.4 Gy (range 3.5-63.4). The median mean dose to the contralateral hippocampus, expressed as equivalent to a 2-Gy dose (EQD 2/2 ), was 7.4 Gy 2 (0.7-13.1). The mean relative changes in SVLT-TR, SVLT-DR, and SVLT-Recognition at seven months compared to the baseline were - 7.7% (95% confidence interval [CI], - 19.6% to 4.2%), - 9.2% (95% CI, - 25.4% to 7.0%), and - 3.4% (- 12.7% to 5.8%), respectively. Two patients (7.7%) showed deteriorated NCF in the SVLT-TR and SVLT-DR, and three (11.5%) in the SVLT-Recognition. The mean dose of the left hippocampus and bilateral hippocampi were significantly higher in patients showing deterioration of the SVLT-TR and SVLT-Recognition than in those without deterioration., Conclusions: The contralateral hippocampus could be effectively spared in patients with primary brain tumor via VMAT to preserve the verbal memory function. Further investigation is needed to identify those patients who will most benefit from hippocampal-sparing radiotherapy of the primary brain tumor.

Background: To derive and exploit the optimal prescription isodose level (PIL) in inverse optimization of volumetric modulated arc radiotherapy (VMAT) as a potential approach to dose de-escalation in stereotactic body radiotherapy for non-small cell lung carcinomas (NSCLC)., Methods: For ten patients, inverse Monte Carlo dose optimization was performed to cover 95% PTV by varying prescription isodose lines (PIL) at 60 to 80% and reference 85%. Subsequently, these were re-normalized to the median gross tumor volume dose (GTV-based prescription) to assess the impacts of PTV and normal tissue dose reduction., Results: With PTV-based prescription, GTV mean dose was much higher with the optimized PIL at 60% with significant reduction of normal lung receiving 30 to 10 Gy (V 30-10Gy ), and observable but insignificant dose reduction to spinal cord, esophagus, ribs, and others compared with 85% PIL. Mean doses to the normal lung between PTV and GTV was higher with 60-70% PIL than 85%. The dose gradient index was 5.0 ± 1.1 and 6.1 ± 1.4 for 60 and 85% PIL (p < 0.05), respectively. Compared with the reference 85% PIL plan using PTV-base prescription, significant decreases of all normal tissue doses were observed with 60% and 70% PIL by GTV-based prescription. Yet, the resulting biological effective (BED) mean doses of PTV remain sufficiently high, ranging 104.2 to 116.9 Gy α/β = 10 ., Conclusions: Optimizing the PIL with VMAT has notable advantage of improving the dosimetric quality of lung SBRT and offers the potential of dose de-escalation for surrounding tissues while increasing the GTV dose simultaneously. The clinical implication of re-normalizing plans from PTV-prescription at 60-70% to the GTV median dose requires further investigations.

Background: Knowledge-based planning (KBP) is a promising technique that can improve plan quality and increase planning efficiency. However, no attempts have been made to extend the domain of KBP for planners with different planning experiences so far. The purpose of this study was to quantify the potential gains for planners with different planning experiences after implementing KBP in intensity modulated radiation therapy (IMRT) plans for left-sided breast cancer patients., Methods: The model libraries were populated with 80 expert clinical plans from treated patients who previously received left-sided breast-conserving surgery and IMRT with simultaneously integrated boost. The libraries were created on the RapidPlan TM . 6 planners with different planning experiences (2 beginner planners, 2 junior planners and 2 senior planners) generated manual and KBP optimized plans for additional 10 patients, similar to those included in the model libraries. The plan qualities were compared between manual and KBP plans., Results: All plans were capable of achieving the prescription requirement. There were almost no statistically significant differences in terms of the planning target volume (PTV) coverage and dose conformality. It was demonstrated that the doses for most of organs-at-risk (OARs) were on average lower or equal in KBP plans compared to manual plans except for the senior planners, where the very small differences were not statistically significant. KBP data showed a systematic trend to have superior dose sparing at most parameters for the heart and ipsilateral lung. The observed decrease in the doses to these OARs could be achieved, particularly for the beginner and junior planners. Many differences were statistically significant., Conclusions: It is feasible to generate acceptable IMRT plans after implementing KBP for left-sided breast cancer. KBP helps to effectively improve the quality of IMRT plans against the benchmark of manual plans for less experienced planners without any manual intervention. KBP showed promise for homogenizing the plan quality by transferring planning expertise from more experienced to less experienced planners.

Background: In volumetric modulated arc therapy (VMAT), gantry angles, dose rate and the MLC positions vary with the radiation delivery. The quality assurance (QA) system should be able to catch the planning and machine errors. The aim of this study was to investigate the sensitivity of three VMAT QA systems to machine errors., Methods: Several types of potential linac machine errors unique to VMAT delivery were simulated in sinusoidal function of gantry angle, including gantry angle itself, MLC position and linac output. Two commercial QA systems, ArcCheck and Delta 4 , and an in-house developed EPID technique were compared in this study. Fifteen full arcs from head and neck plans were selected and modified to include five magnitudes of each type of error, resulting in measurements and γ analyses of 240 arcs on each system. Both qualitative and quantitative comparisons were performed using receiver operating characteristic (ROC), γ pass rate gradient, and overlap histogram methods., Results: In ROC analysis, the area under curve (AUC) represents the sensitivity and increases with the error magnitude. Using the criteria of 2 %/2 mm/2° (angle to agreement, ATA, only for EPID) and keeping AUC > 0.95, the minimum error detectable of ArcCheck, Delta 4 and EPID are (2, 3, 3)° in gantry angle and (4, 2, 3) mm in MLC positions for the head and neck plans. No system is sensitive to the simulated output error, the AUC values were all below 0.70 even with 5 % output error. The γ gradient for gantry angle, MLC position and output errors are (-5.1, -2.6, -3.6)%/°, (-2.6, -7.1, -3.3)%/mm and (-0.2, -0.2, -0.3)%/% for ArcCheck, Delta 4 and EPID, respectively. Therefore, these two analyses are consistent and support the same conclusion. The ATA parameter in EPID technique can be adjusted to tune its sensitivity., Conclusions: We found that ArcCheck is more sensitive to gantry angle error and Delta 4 is more sensitive to MLC position error. All three systems are not sensitive to the simulated output error. With additional analysis parameter, the EPID technique can be tuned to have optimal sensitivity and is able to perform QA for full field size with highest resolution. In addition, ROC analysis avoids the choice of γ pass rate threshold and is more robust compared with other analysis methods.

Background: O-(2-18 F-fluoroethyl)-L-tyrosine-(FET)-PET may be helpful to improve the definition of radiation target volumes in glioblastomas compared with MRI. We analyzed the relapse patterns in FET-PET after a FET- and MRI-based integrated-boost intensity-modulated radiotherapy (IMRT) of glioblastomas to perform an optimized target volume definition., Methods: A relapse pattern analysis was performed in 13 glioblastoma patients treated with radiochemotherapy within a prospective phase-II-study between 2008 and 2009. Radiotherapy was performed as an integrated-boost intensity-modulated radiotherapy (IB-IMRT). The prescribed dose was 72 Gy for the boost target volume, based on baseline FET-PET (FET-1) and 60 Gy for the MRI-based (MRI-1) standard target volume. The single doses were 2.4 and 2.0 Gy, respectively. Location and volume of recurrent tumors in FET-2 and MRI-2 were analyzed related to initial tumor, detected in baseline FET-1. Variable target volumes were created theoretically based on FET-1 to optimally cover recurrent tumor., Results: The tumor volume overlap in FET and MRI was poor both at baseline (median 12 %; range 0-32) and at time of recurrence (13 %; 0-100). Recurrent tumor volume in FET-2 was localized to 39 % (12-91) in the initial tumor volume (FET-1). Over the time a shrinking (mean 12 (5-26) ml) and shifting (mean 6 (1-10 mm) of the resection cavity was seen. A simulated target volume based on active tumor in FET-1 with an additional safety margin of 7 mm around the FET-1 volume covered recurrent FET tumor volume (FET-2) significantly better than a corresponding target volume based on contrast enhancement in MRI-1 with a same safety margin of 7 mm (100 % (54-100) versus 85 % (0-100); p < 0.01). A simulated planning target volume (PTV), based on FET-1 and additional 7 mm margin plus 5 mm margin for setup-uncertainties was significantly smaller than the conventional, MR-based PTV applied in this study (median 160 (112-297) ml versus 231 (117-386) ml, p < 0.001)., Conclusions: In this small study recurrent tumor volume in FET-PET (FET-2) overlapped only to one third with the boost target volume, based on FET-1. The shrinking and shifting of the resection cavity may have an influence considering the limited overlap of initial and relapse tumor volume. A simulated target volume, based on FET-1 with 7 mm margin covered 100 % of relapse volume in median and led to a significantly reduced PTV, compared to MRI-based PTVs. This approach may achieve similar therapeutic efficacy but lower side effects offering a broader window to intensify concomitant systemic treatment focusing distant failures.

Objectives: To demonstrate that novice dosimetry planners efficiently create clinically acceptable IMRT plans for head and neck cancer (HNC) patients using a commercially available multicriteria optimization (MCO) system., Methods: Twenty HNC patients were enrolled in this in-silico comparative planning study. Per patient, novice planners with less experience in dosimetry planning created an IMRT plan using an MCO system (RayStation). Furthermore, a conventionally planned clinical IMRT plan was available (Pinnacle(3)). All conventional IMRT and MCO-plans were blind-rated by two expert radiation-oncologists in HNC, using a 5-point scale (1-5 with 5 the highest score) assessment form comprising 10 questions. Additionally, plan quality was reported in terms of planning time, dosimetric and normal tissue complication probability (NTCP) comparisons. Inter-rater reliability was derived using the intra-class correlation coefficient (ICC)., Results: In total, the radiation-oncologists rated 800 items on plan quality. The overall plan score indicated no differences between both planning techniques (conventional IMRT: 3.8 ± 1.2 vs. MCO: 3.6 ± 1.1, p = 0.29). The inter-rater reliability of all ratings was 0.65 (95% CI: 0.57-0.71), indicating substantial agreement between the radiation-oncologists. In 93% of cases, the scoring difference of the conventional IMRT and MCO-plans was one point or less. Furthermore, MCO-plans led to slightly higher dose uniformity in the therapeutic planning target volume, to a lower integral body dose (13.9 ± 4.5 Gy vs. 12.9 ± 4.0 Gy, p < 0.001), and to reduced dose to the contra-lateral parotid gland (28.1 ± 11.8 Gy vs. 23.0 ± 11.2 Gy, p < 0.002). Consequently, NTCP estimates for xerostomia reduced by 8.4 ± 7.4% (p < 0.003). The hands-on time of the conventional IMRT planning was approximately 205 min. The time to create an MCO-plan was on average 43 ± 12 min., Conclusions: MCO planning enables novice treatment planners to create high quality IMRT plans for HNC patients. Plans were created with vastly reduced planning times, requiring less resources and a short learning curve.

Background: Intensity modulated radiotherapy treatment planning for sites with many different organs-at-risk (OAR) is complex and labor-intensive, making it hard to obtain consistent plan quality. With the aim of addressing this, we developed a program (automatic interactive optimizer, AIO) designed to automate the manual interactive process for the Eclipse treatment planning system. We describe AIO and present initial evaluation data., Methods: Our current institutional volumetric modulated arc therapy (RapidArc) planning approach for head and neck tumors places 3-4 adjustable OAR optimization objectives along the dose-volume histogram (DVH) curve that is displayed in the optimization window. AIO scans this window and uses color-coding to differentiate between the DVH-lines, allowing it to automatically adjust the location of the optimization objectives frequently and in a more consistent fashion. We compared RapidArc AIO plans (using 9 optimization objectives per OAR) with the clinical plans of 10 patients, and evaluated optimal AIO settings. AIO consistency was tested by replanning a single patient 5 times., Results: Average V95&V107 of the boost planning target volume (PTV) and V95 of the elective PTV differed by ≤0.5%, while average elective PTV V107 improved by 1.5%. Averaged over all patients, AIO reduced mean doses to individual salivary structures by 0.9-1.6Gy and provided mean dose reductions of 5.6Gy and 3.9Gy to the composite swallowing structures and oral cavity, respectively. Re-running AIO five times, resulted in the aforementioned parameters differing by less than 3%., Conclusions: Using the same planning strategy as manually optimized head and neck plans, AIO can automate the interactive Eclipse treatment planning process and deliver dosimetric improvements over existing clinical plans.

Background: To evaluate in-silico the performance of a model-based optimization process for volumetric modulated arc therapy (RapidArc) applied to hepatocellular cancer treatments., Patients and Methods: 45 clinically accepted RA plans were selected to train a knowledge-based engine for the prediction of individualized dose-volume constraints. The model was validated on the same plans used for training (closed-loop) and on a set of other 25 plans not used for the training (open-loop). Dose prescription, target size, localization in the liver and arc configuration were highly variable in both sets to appraise the power of generalization of the engine. Quantitative dose volume histogram analysis was performed as well as a pass-fail analysis against a set of 8 clinical dose-volume objectives to appraise the quality of the new plans., Results: Qualitative and quantitative equivalence was observed between the clinical and the test plans. The use of model-based optimization lead to a net improvement in the pass-rate of the clinical objectives compared to the plans originally optimized with standard methods (this pass-rate is the frequency of cases where the objectives are respected vs. the cases where constraints are not fulfilled). The increase in the pass-rate resulted of 2.0%, 0.9% and 0.5% in a closed-loop and two different open-loop validation experiments., Conclusions: A knowledge-based engine for the optimization of RapidArc plans was tested and lead to clinically acceptable plans in the case of hepatocellular cancer radiotherapy. More studies are needed before a broad clinical use.

Background: To investigate the sensitivity of various gamma criteria used in the gamma-index method for patient-specific volumetric modulated arc therapy (VMAT) quality assurance (QA) for stereotactic body radiation therapy (SBRT) using a flattening filter free (FFF) photon beam., Methods: Three types of intentional misalignments were introduced to original high-definition multi-leaf collimator (HD-MLC) plans. The first type, referred to Class Out, involved the opening of each bank of leaves. The second type, Class In, involved the closing of each bank of leaves. The third type, Class Shift, involved the shifting of each bank of leaves towards the ground. Patient-specific QAs for the original and the modified plans were performed with MapCHECK2 and EBT2 films. The sensitivity of the gamma-index method using criteria of 1%/1 mm, 1.5%/1.5 mm, 1%/2 mm, 2%/1 mm and 2%/2 mm was investigated with absolute passing rates according to the magnitudes of MLCs misalignments. In addition, the changes in dose-volumetric indicators due to the magnitudes of MLC misalignments were investigated. The correlations between passing rates and the changes in dose-volumetric indicators were also investigated using Spearman's rank correlation coefficient (γ)., Results: The criterion of 2%/1 mm was able to detect Class Out and Class In MLC misalignments of 0.5 mm and Class Shift misalignments of 1 mm. The widely adopted clinical criterion of 2%/2 mm was not able to detect 0.5 mm MLC errors of the Class Out or Class In types, and also unable to detect 3 mm Class Shift errors. No correlations were observed between dose-volumetric changes and gamma passing rates (γ < 0.8)., Conclusions: Gamma criterion of 2%/1 mm was found to be suitable as a tolerance level with passing rates of 90% and 80% for patient-specific VMAT QA for SBRT when using MapCHECK2 and EBT2 film, respectively.

Background: Stereotactic Radiosurgery (SRS) is a common tool used to treat Arteriovenous Malformations (AVMs) in anatomical locations associated with a risk of surgical complications. Despite high rates of clinical effectiveness, SRS carries a risk of toxicity as a result of radiation injury to brain tissue. The use of intensity-modulated radiotherapy (IMRT) has increased because it may lead to improved PTV conformity and better Normal Tissue (NT) sparing compared to 3D Conformal Radiotherapy (3DCRT). The aim of this study was twofold: 1) to develop simple patient stratification rules for the recommendation of IMRT planning strategies over 3DCRT in the treatment of AVMs with SRS; and 2) to estimate the impact of IMRT in terms of toxicity reduction using retrospectively reported data for symptomatic radiation injury following SRS., Methods: Thirty-one AVM patients previously treated with 3DCRT were replanned in a commercial treatment planning system using 3DCRT and static gantry IMRT with identical beam arrangements. The radiotherapy planning metrics analyzed included AVM volume, diameter, and volume to surface area ratio. The dosimetric endpoints analyzed included conformity index improvements and NT sparing measured by the maximum NT dose, and the volume of surrounding tissue that received 7Gy and 12Gy., Results: Our analysis revealed stratified subsets of patients for IMRT that were associated with improved conformity, and those that were associated with decreased doses to normal tissue. The stratified patients experienced an improvement in conformity index by -6-68%, a reduction in the maximum NT dose by -0.5-12.3%, a reduction in the volume of NT receiving 7Gy by 1-8 cc, and a reduction in the volume of NT receiving 12Gy by 0-3.7 cc. The reduction in NT receiving 12Gy translated to a theoretical decrease in the probability of symptomatic injury by 0-9.3%., Conclusions: This work indicates the potential for significant patient improvements when treating AVMs and provides rules to predict which patients are likely to benefit from IMRT.

Background: Since December 2009 a new VMAT planning system tool is available in Oncentra MasterPlan v3.3 (Nucletron B.V.). The purpose of this study was to work out standard parameters for the optimization of prostate cancer., Methods: For ten patients with localized prostate cancer plans for simultaneous integrated boost were optimized, varying systematically the number of arcs, collimator angle, the maximum delivery time, and the gantry spacing. Homogeneity in clinical target volume, minimum dose in planning target volume, median dose in the organs at risk, maximum dose in the posterior part of the rectum, and number of monitor units were evaluated using student's test for statistical analysis. Measurements were performed with a 2D-array, taking the delivery time, and compared to the calculation by the gamma method., Results: Plans with collimator 45° were superior to plans with collimator 0°. Single arc resulted in higher minimum dose in the planning target volume, but also higher dose values to the organs at risk, requiring less monitor units per fraction dose than dual arc. Single arc needs a higher value (per arc) for the maximum delivery time parameter than dual arc, but as only one arc is needed, the measured delivery time was shorter and stayed below 2.5 min versus 3 to 5 min. Balancing plan quality, dosimetric results and calculation time, a gantry spacing of 4° led to optimal results., Conclusion: A set of parameters has been found which can be used as standard for volumetric modulated arc therapy planning of prostate cancer.

Purpose: To establish our institutional guideline for IMRT delivery, we statistically evaluated the results of dosimetry quality assurance (DQA) measurements and derived local confidence limits using the concept confidence limit of |mean|+1.96σ., Materials and Methods: From June 2006 to March 2009, 206 patients with head and neck cancer, prostate cancer, liver cancer, or brain tumor were treated using LINAC-based IMRT technique. In order to determine site specific DQA tolerances at a later stage, a hybrid plan with the same fluence maps as in the treatment plan was generated on CT images of a cylindrical phantom of acryl. Points of measurement using a 0.125 cm3 ion-chamber were typically located in the region of high and uniform doses. The planar dose distributions perpendicular to the central axis were measured by using a diode array in solid water with all fields delivered, and assessed using gamma criteria of 3%/3 mm. The mean values and standard deviations were used to develop the local confidence and tolerance limits. The dose differences and gamma pass rates for the different treatment sites were also evaluated in terms of total monitor uints (MU), MU/cGy, and the number of PTV's pieces., Results: The mean values and standard deviations of ion-chamber dosimetry differences between calculated and measured doses were -1.6 ± 1.2% for H&N cancer, -0.4 ± 1.2% for prostate and abdominal cancer, and -0.6 ± 1.5% for brain tumor. Most of measured doses (92.2%) agreed with the calculated doses within a tolerance limit of ±3% recommended in the literature. However, we found some systematic under-dosage for all treatment sites. The percentage of points passing the gamma criteria, averaged over all treatment sites was 97.3 ± 3.7%. The gamma pass rate and the agreement of ion-chamber dosimetry generally decreased with increasing the number of PTV's pieces, the degree of modulation (MU/cGy), and the total MU beyond 700. Our local confidence limits were comparable to those of AAPM TG 119 and ESTRO guidelines that were provided as a practical baseline for center-to-center commissioning comparison. Thus, our institutional confidence and action limits for IMRT delivery were set into the same levels of those guidelines., Discussion and Conclusions: The systematic under-dosage were corrected by tuning up the MLC-related factors (dosimetric gap and transmission) in treatment planning system (TPS) and further by incorporating the tongue-and groove effect into TPS. Institutions that have performed IMRT DQA measurements over a certain period of time need to analyze their accrued DQA data. We confirmed the overall integrity of our IMRT system and established the IMRT delivery guideline during this procedure. Dosimetric corrections for the treatment plans outside of the action level can be suggested only with such rigorous DQA and statistical analysis., (© 2011 Chung et al; licensee BioMed Central Ltd.)

Purpose: To verify the dose distribution and number of monitor units (MU) for dynamic treatment techniques like volumetric modulated single arc radiation therapy-Rapid Arc-each patient treatment plan has to be verified prior to the first treatment. The purpose of this study was to develop a patient related treatment plan verification protocol using a two dimensional ionization chamber array (MatriXX, IBA, Schwarzenbruck, Germany)., Method: Measurements were done to determine the dependence between response of 2D ionization chamber array, beam direction, and field size. Also the reproducibility of the measurements was checked. For the patient related verifications the original patient Rapid Arc treatment plan was projected on CT dataset of the MatriXX and the dose distribution was calculated. After irradiation of the Rapid Arc verification plans measured and calculated 2D dose distributions were compared using the gamma evaluation method implemented in the measuring software OmniPro (version 1.5, IBA, Schwarzenbruck, Germany)., Results: The dependence between response of 2D ionization chamber array, field size and beam direction has shown a passing rate of 99% for field sizes between 7 cm×7 cm and 24 cm×24 cm for measurements of single arc. For smaller and larger field sizes than 7 cm×7 cm and 24 cm×24 cm the passing rate was less than 99%. The reproducibility was within a passing rate of 99% and 100%. The accuracy of the whole process including the uncertainty of the measuring system, treatment planning system, linear accelerator and isocentric laser system in the treatment room was acceptable for treatment plan verification using gamma criteria of 3% and 3 mm, 2D global gamma index., Conclusion: It was possible to verify the 2D dose distribution and MU of Rapid Arc treatment plans using the MatriXX. The use of the MatriXX for Rapid Arc treatment plan verification in clinical routine is reasonable. The passing rate should be 99% than the verification protocol is able to detect clinically significant errors.

Background: ICRU 50/62 provides a framework to facilitate the reporting of external beam radiotherapy treatments from different institutions. A predominant role is played by points that represent "the PTV dose". However, for new techniques like Intensity Modulated Radiotherapy (IMRT) - especially step and shoot IMRT - it is difficult to define a point whose dose can be called "characteristic" of the PTV dose distribution. Therefore different volume based methods of reporting of the prescribed dose are in use worldwide. Several of them were compared regarding their usability for IMRT and compatibility with the ICRU Reference Point dose for conformal radiotherapy (CRT) in this study., Methods: The dose distributions of 45 arbitrarily chosen volumes treated by CRT plans and 57 volumes treated by IMRT plans were used for comparison. Some of the IMRT methods distinguish the planning target volume (PTV) and its central part PTVx (PTV minus a margin region of x mm). The reporting of dose prescriptions based on mean and median doses together with the dose to 95% of the considered volume (D95) were compared with each other and in respect of a prescription report with the aid of one or several possible ICRU Reference Points. The correlation between all methods was determined using the standard deviation of the ratio of all possible pairs of prescription reports. In addition the effects of boluses and the characteristics of simultaneous integrated boosts (SIB) were examined., Results: Two types of methods result in a high degree of consistency with the hitherto valid ICRU dose reporting concept: the median dose of the PTV and the mean dose to the central part of the PTV (PTVx). The latter is similar to the CTV, if no nested PTVs are used and no patient model surfaces are involved. A reporting of dose prescription using the CTV mean dose tends to overestimate the plateau doses of the lower dose plateaus of SIB plans. PTVx provides the possibility to approach biological effects using the standard deviation of the dose within this volume., Conclusion: The authors advocate reporting the PTV median dose or preferably the mean dose of the central dose plateau PTVx as a potential replacement or successor of the ICRU Reference Dose - both usable for CRT and IMRT.

Intensity Modulated Radiation Therapy (IMRT) is a means of delivering radiation therapy where the intensity of the beam is varied within the treatment field. This is done by dividing a large beam into many small beamlets. Dose constraints are assigned to both the target and sensitive structures and computerised inverse optimization is performed to find the individual weights of this large number of beamlets. The computer adjusts the intensities of these beamlets according to the required planning dose objectives. The optimized intensity patterns are then decomposed into a series of deliverable multi leaf collimator (MLC) shapes in the sequencing step. One of the main problems of IMRT, which becomes even more apparent as the complexity of the IMRT plan increases, is the dramatic increase in the number of Monitor Units (MU) required to deliver a fractionated treatment. The difficulty with this increase in MU is its association with increased treatment times and a greater leakage of radiation from the MLCs increasing the total body dose and the risk of secondary cancers in patients. Therefore one attempts to find ways of reducing these MU without compromising plan quality. The design of inverse planning systems where the beam is divided into small beamlets to produce the required intensity map automatically introduces complexity into IMRT treatment planning. Plan complexity is associated with many negative factors such as dosimetric uncertainty and delivery issues A large search space is required necessitating much computing power. However, the limitations of the delivery technology are not taken into consideration when designing the ideal intensity map therefore a further step termed the sequencing step is required to convert the ideal intensity map into a deliverable one. Many approaches have been taken to reduce the complexity. These include setting intensity limits, putting penalties on the cost function and using smoothing filters Direct Aperture optimization (DAO) incorporates the limitations of the delivery technology at the initial design of the intensity map thereby eliminating the sequencing step. It also gives control over the number of segments and hence control over the complexity of the plan although the design of the segments is independent of the person preparing the plan.