Prostate cancer and elective nodal radiation therapy for cN0 and pN0-a never ending story? : Recommendations from the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO).

For prostate cancer, the role of elective nodal irradiation (ENI) for cN0 or pN0 patients has been under discussion for years. Considering the recent publications of randomized controlled trials, the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO) aimed to discuss and summarize the current literature. Modern trials have been recently published for both treatment-naïve patients (POP-RT trial) and patients after surgery (SPPORT trial). Although there are more reliable data to date, we identified several limitations currently complicating the definitions of general recommendations. For patients with cN0 (conventional or PSMA-PET staging) undergoing definitive radiotherapy, only men with high-risk factors for nodal involvement (e.g., cT3a, GS ≥ 8, PSA ≥ 20 ng/ml) seem to benefit from ENI. For biochemical relapse in the postoperative situation (pN0) and no PSMA imaging, ENI may be added to patients with risk factors according to the SPPORT trial (e.g., GS ≥ 8; PSA > 0.7 ng/ml). If PSMA-PET/CT is negative, ENI may be offered for selected men with high-risk factors as an individual treatment approach.

Efficiency enhancements of a Monte Carlo beamlet based treatment planning process: implementation and parameter study.

Objective.The computational effort to perform beamlet calculation, plan optimization and final dose calculation of a treatment planning process (TPP) generating intensity modulated treatment plans is enormous, especially if Monte Carlo (MC) simulations are used for dose calculation. The goal of this work is to improve the computational efficiency of a fully MC based TPP for static and dynamic photon, electron and mixed photon-electron treatment techniques by implementing multiple methods and studying the influence of their parameters.Approach.A framework is implemented calculating MC beamlets efficiently in parallel on each available CPU core. The user can specify the desired statistical uncertainty of the beamlets, a fractional sparse dose threshold to save beamlets in a sparse format and minimal distances to the PTV surface from which 2 × 2 × 2 = 8 (medium) or even 4 × 4 × 4 = 64 (large) voxels are merged. The compromise between final plan quality and computational efficiency of beamlet calculation and optimization is studied for several parameter values to find a reasonable trade-off. For this purpose, four clinical and one academic case are considered with different treatment techniques.Main results.Setting the statistical uncertainty to 5% (photon beamlets) and 15% (electron beamlets), the fractional sparse dose threshold relative to the maximal beamlet dose to 0.1% and minimal distances for medium and large voxels to the PTV to 1 cm and 2 cm, respectively, does not lead to substantial degradation in final plan quality compared to using 2.5% (photon beamlets) and 5% (electron beamlets) statistical uncertainty and no sparse format nor voxel merging. Only OAR sparing is slightly degraded. Furthermore, computation times are reduced by about 58% (photon beamlets), 88% (electron beamlets) and 96% (optimization).Significance.Several methods are implemented improving computational efficiency of beamlet calculation and plan optimization of a fully MC based TPP without substantial degradation in final plan quality.

Enabling non-isocentric dynamic trajectory radiotherapy by integration of dynamic table translations.

Objective.The purpose of this study is to develop a treatment planning process (TPP) for non-isocentric dynamic trajectory radiotherapy (DTRT) using dynamic gantry rotation, collimator rotation, table rotation, longitudinal, vertical and lateral table translations and intensity modulation and to validate the dosimetric accuracy.Approach.The TPP consists of two steps. First, a path describing the dynamic gantry rotation, collimator rotation and dynamic table rotation and translations is determined. Second, an optimization of the intensity modulation along the path is performed. We demonstrate the TPP for three use cases. First, a non-isocentric DTRT plan for a brain case is compared to an isocentric DTRT plan in terms of dosimetric plan quality and delivery time. Second, a non-isocentric DTRT plan for a craniospinal irradiation (CSI) case is compared to a multi-isocentric intensity modulated radiotherapy (IMRT) plan. Third, a non-isocentric DTRT plan for a bilateral breast case is compared to a multi-isocentric volumetric modulated arc therapy (VMAT) plan. The non-isocentric DTRT plans are delivered on a TrueBeam in developer mode and their dosimetric accuracy is validated using radiochromic films.Main results.The non-isocentric DTRT plan for the brain case is similar in dosimetric plan quality and delivery time to the isocentric DTRT plan but is expected to reduce the risk of collisions. The DTRT plan for the CSI case shows similar dosimetric plan quality while reducing the delivery time by 45% in comparison with the IMRT plan. The DTRT plan for the breast case showed better treatment plan quality in comparison with the VMAT plan. The gamma passing rates between the measured and calculated dose distributions are higher than 95% for all three plans.Significance.The versatile benefits of non-isocentric DTRT are demonstrated with three use cases, namely reduction of collision risk, reduced setup and delivery time and improved dosimetric plan quality.

Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

A hybrid column generation and simulated annealing algorithm for direct aperture optimization.

The purpose of this work was to develop a hybrid column generation (CG) and simulated annealing (SA) algorithm for direct aperture optimization (H-DAO) and to show its effectiveness in generating high quality treatment plans for intensity modulated radiation therapy (IMRT) and mixed photon-electron beam radiotherapy (MBRT). The H-DAO overcomes limitations of the CG-DAO with two features improving aperture selection (branch-feature) and enabling aperture shape changes during optimization (SA-feature). The H-DAO algorithm iteratively adds apertures to the plan. At each iteration, a branch is created for each field provided. First, each branch determines the most promising aperture of its assigned field and adds it to a copy of the current apertures. Afterwards, the apertures of each branch undergo an MU-weight optimization followed by an SA-based simultaneous shape and MU-weight optimization and a second MU-weight optimization. The next H-DAO iteration continues the branch with the lowest objective function value. IMRT and MBRT treatment plans for an academic, a brain and a head and neck case generated using the CG-DAO and H-DAO were compared. For every investigated case and both IMRT and MBRT, the H-DAO leads to a faster convergence of the objective function value with number of apertures compared to the CG-DAO. In particular, the H-DAO needs about half the apertures to reach the same objective function value as the CG-DAO. The average aperture areas are 27% smaller for H-DAO than for CG-DAO leading to a slightly larger discrepancy between optimized and final dose. However, a dosimetric benefit remains. The H-DAO was successfully developed and applied to IMRT and MBRT. The faster convergence with number of apertures of the H-DAO compared to the CG-DAO allows to select a better compromise between plan quality and number of apertures.

TriB-RT: Simultaneous optimization of photon, electron and proton beams.

PURPOSE: To develop a novel treatment planning process (TPP) with simultaneous optimization of modulated photon, electron and proton beams for improved treatment plan quality in radiotherapy. METHODS: A framework for fluence map optimization of Monte Carlo (MC) calculated beamlet dose distributions is developed to generate treatment plans consisting of photon, electron and spot scanning proton fields. Initially, in-house intensity modulated proton therapy (IMPT) plans are compared to proton plans created by a commercial treatment planning system (TPS). A triple beam radiotherapy (TriB-RT) plan is generated for an exemplary academic case and the dose contributions of the three particle types are investigated. To investigate the dosimetric potential, a TriB-RT plan is compared to an in-house IMPT plan for two clinically motivated cases. Benefits of TriB-RT for a fixed proton beam line with a single proton field are investigated. RESULTS: In-house optimized IMPT are of at least equal or better quality than TPS-generated proton plans, and MC-based optimization shows dosimetric advantages for inhomogeneous situations. Concerning TriB-RT, for the academic case, the resulting plan shows substantial contribution of all particle types. For the clinically motivated case, improved sparing of organs at risk close to the target volume is achieved compared to IMPT (e.g. myelon and brainstem [Formula: see text] -37%) at cost of an increased low dose bath (healthy tissue V 10% +22%). In the scenario of a fixed proton beam line, TriB-RT plans are able to compensate the loss in degrees of freedom to substantially improve plan quality compared to a single field proton plan. CONCLUSION: A novel TPP which simultaneously optimizes photon, electron and proton beams was successfully developed. TriB-RT shows the potential for improved treatment plan quality and is especially promising for cost-effective single-room proton solutions with a fixed beamline in combination with a conventional linac delivering photon and electron fields.

A cost-effectiveness analysis of consolidation immunotherapy with durvalumab in stage III NSCLC responding to definitive radiochemotherapy in Switzerland.

BACKGROUND: Consolidation immunotherapy with the programmed death ligand 1 (PD-L1) inhibitor durvalumab improves survival in patients with stage III non-small-cell lung cancer responding to radiochemotherapy. The aim of this study was to assess the cost-effectiveness of durvalumab in Switzerland based on the most recent PACIFIC survival follow-up. MATERIALS AND METHODS: We constructed a Markov model based on the 3-year follow-up data of the PACIFIC trial and compared consolidation durvalumab with observation. We used published utility values and assessed costs for treatment strategies from the perspective of the Swiss health care payers. Cost-effectiveness was tested both in the intention-to-treat population of the PACIFIC trial unselected for PD-L1 tumor expression and in patients with PD-L1-expressing tumors (≥1%). RESULTS: In the unselected/PD-L1-positive patients, durvalumab showed an incremental effectiveness of 0.76/1.18 quality-adjusted life year (QALY) and incremental costs of Swiss Francs (CHF) 67 239/78 177, resulting in incremental cost-effectiveness ratios of CHF 88 703/66 131 per QALY gained, respectively. The most influential factors for the incremental cost-effectiveness ratio were the utility before first progression, costs for durvalumab, and the hazard ratio for overall survival under durvalumab versus observation. The cost-effectiveness of durvalumab was better than CHF 100 000 per QALY gained in 75% of the simulations in probabilistic sensitivity analysis. CONCLUSION: Assuming a willingness-to-pay threshold of CHF 100 000 per QALY gained, consolidation durvalumab is likely to be cost-effective both in patients with inoperable stage III non-small-cell lung cancer (NSCLC) unselected for PD-L1 status and in patients with PD-L1-expressing tumors in Switzerland.

Benchmarking Monte-Carlo dose calculation for MLC CyberKnife treatments.

BACKGROUND: Vendor-independent Monte Carlo (MC) dose calculation (IDC) for patient-specific quality assurance of multi-leaf collimator (MLC) based CyberKnife treatments is used to benchmark and validate the commercial MC dose calculation engine for MLC based treatments built into the CyberKnife treatment planning system (Precision MC). METHODS: The benchmark included dose profiles in water in 15 mm depth and depth dose curves of rectangular MLC shaped fields ranging from 7.6 mm × 7.7 mm to 115.0 mm × 100.1 mm, which were compared between IDC, Precision MC and measurements in terms of dose difference and distance to agreement. Dose distributions of three phantom cases and seven clinical lung cases were calculated using both IDC and Precision MC. The lung PTVs ranged from 14 cm3 to 93 cm3. Quantitative comparison of these dose distributions was performed using dose-volume parameters and 3D gamma analysis with 2% global dose difference and 1 mm distance criteria and a global 10% dose threshold. Time to calculate dose distributions was recorded and efficiency was assessed. RESULTS: Absolute dose profiles in 15 mm depth in water showed agreement between Precision MC and IDC within 3.1% or 1 mm. Depth dose curves agreed within 2.3% / 1 mm. For the phantom and clinical lung cases, mean PTV doses differed from - 1.0 to + 2.3% between IDC and Precision MC and gamma passing rates were > =98.1% for all multiple beam treatment plans. For the lung cases, lung V20 agreed within ±1.5%. Calculation times ranged from 2.2 min (for 39 cm3 PTV at 1.0 × 1.0 × 2.5 mm3 native CT resolution) to 8.1 min (93 cm3 at 1.1 × 1.1 × 1.0 mm3), at 2% uncertainty for Precision MC for the 7 examined lung cases and 4-6 h for IDC, which, however, is not optimized for efficiency but used as a gold standard for accuracy. CONCLUSIONS: Both accuracy and efficiency of Precision MC in the context of MLC based planning for the CyberKnife M6 system were benchmarked against MC based IDC framework. Precision MC is used in clinical practice at our institute.

Impact of regular magnetic resonance imaging follow-up after stereotactic radiotherapy to the surgical cavity in patients with one to three brain metastases.

BACKGROUND: Administering stereotactic radiotherapy to the surgical cavity and thus omitting postoperative whole brain radiotherapy (WBRT) is a favored strategy in limited metastatic brain disease. Little is known about the impact of regular magnetic resonance imaging follow-up (MRI FU) in such patient cohorts. The aim of this study is to examine the impact of regular MRI FU and to report the oncological outcomes of patients with one to three brain metastases (BMs) treated with stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic radiotherapy (HFSRT) to the surgical cavity. METHODS: We retrospectively analyzed patients who received SRS or HFSRT to the surgical cavity after resection of one to two BMs. Additional, non-resected BMs were managed with SRS alone. Survival was estimated by the Kaplan-Meier method. Prognostic factors were examined with the log-rank test and Cox proportional hazards model. Regular MRI FU was defined as performing a brain MRI 3 months after radiotherapy (RT) and/or performing ≥1 brain MRI per 180 days. Primary endpoint was local control (LC). Secondary endpoints were distant brain control (DBC), overall survival (OS) and the correlation between regular MRI FU and overall survival (OS), symptom-free survival (SFS), deferment of WBRT and WBRT-free survival (WFS). RESULTS: Overall, 75 patients were enrolled. One, 2 and 3 BMs were seen in 63 (84%), 11 (15%) and 1 (1%) patients, respectively. Forty (53%) patients underwent MRI FU 3 months after RT and 38 (51%) patients received ≥1 brain MRI per 180 days. Median OS was 19.4 months (95% CI: 13.2-25.6 months). Actuarial LC, DBC and OS at 1 year were 72% (95% CI: 60-83%), 60% (95% CI: 48-72%) and 66% (95% CI: 53-76%), respectively. A planning target volume > 15 cm3 (p = 0.01), Graded Prognostic Assessment (GPA) score (p = 0.001) and residual tumor after surgery (p = 0.008) were prognostic for decreased OS in multivariate analysis. No significant correlation between MRI FU at 3 months and OS (p = 0.462), SFS (p = 0.536), WFS (p = 0.407) or deferment of WBRT (p = 0.955) was seen. Likewise, performing ≥1 MRI per 180 days had no significant impact on OS (p = 0.954), SFS (p = 0.196), WFS (p = 0.308) or deferment of WBRT (p = 0.268). CONCLUSION: Our results regarding oncological outcomes consist with the current data from the literature. Surprisingly, regular MRI FU did not result in increased OS, SFS, WFS or deferment of WBRT in our cohort consisting mainly of patients with a single and resected BM. Therefore, the impact of regular MRI FU needs prospective evaluation. TRIAL REGISTRATION: Project ID: 2017-00033, retrospectively registered.

Accuracy assessment of a potential clinical use of navigation-guided intra-operative liver metastasis brachytherapy-a planning study.

For patients with inoperable liver metastases, intra-operative liver high dose-rate brachytherapy (HDR-BT) is a promising technology enabling delivery of a high radiation dose to the tumor, while sparing healthy tissue. Liver brachytherapy has been described in the literature as safe and effective for the treatment of primary or secondary hepatic malignancies. It is preferred over other ablative techniques for lesions that are either larger than 4 cm or located in close proximity to large vessels or the common bile duct. In contrast to external beam radiation techniques, organ movements do not affect the size of the irradiated volume in intra-operative HDR-BT and new technical solutions exist to support image guidance for intra-operative HDR-BT. We have retrospectively analyzed anonymized CT datasets of 5 patients who underwent open liver surgery (resection and/or ablation) in order to test whether the accuracy of a new image-guidance method specifically adapted for intra-operative HDR-BT is high enough to use it in similar situations and whether patients could potentially benefit from navigation-guided intra-operative needle placement for liver HDR-BT.

Part 2: Dynamic mixed beam radiotherapy (DYMBER): Photon dynamic trajectories combined with modulated electron beams.

PURPOSE: The purpose of this study was to develop a treatment technique for dynamic mixed beam radiotherapy (DYMBER) utilizing increased degrees of freedom (DoF) of a conventional treatment unit including different particle types (photons and electrons), intensity and energy modulation and dynamic gantry, table, and collimator rotations. METHODS: A treatment planning process has been developed to create DYMBER plans combining photon dynamic trajectories (DTs) and step and shoot electron apertures collimated with the photon multileaf collimator (pMLC). A gantry-table path is determined for the photon DTs with minimized overlap of the organs at risk (OARs) with the target. In addition, an associated dynamic collimator rotation is established with minimized area between the pMLC leaves and the target contour. pMLC sequences of photon DTs and electron pMLC apertures are then simultaneously optimized using direct aperture optimization (DAO). Subsequently, the final dose distribution of the electron pMLC apertures is calculated using the Swiss Monte Carlo Plan (SMCP). The pMLC sequences of the photon DTs are then re-optimized with a finer control point resolution and with the final electron dose distribution taken into account. Afterwards, the final photon dose distribution is calculated also using the SMCP and summed together with the one of the electrons. This process is applied for a brain and two head and neck cases. The resulting DYMBER dose distributions are compared to those of dynamic trajectory radiotherapy (DTRT) plans consisting only of photon DTs and clinically applied VMAT plans. Furthermore, the deliverability of the DYMBER plans is verified in terms of dosimetric accuracy, delivery time and collision avoidance. For this purpose, The DYMBER plans are delivered to Gafchromic EBT3 films placed in an anthropomorphic head phantom on a Varian TrueBeam linear accelerator. RESULTS: For each case, the dose homogeneity in the target is similar or better for DYMBER compared to DTRT and VMAT. Averaged over all three cases, the mean dose to the parallel OARs is 16% and 28% lower, D2% to the serial OARs is 17% and 37% lower and V10% to normal tissue is 12% and 4% lower for the DYMBER plans compared to the DTRT and VMAT plans, respectively. The DYMBER plans are delivered without collision and with a 4-5 min longer delivery time than the VMAT plans. The absolute dose measurements are compared to calculation by gamma analysis using 2% (global)/2 mm criteria with passing rates of at least 99%. CONCLUSIONS: A treatment technique for DYMBER has been successfully developed and verified for its deliverability. The dosimetric superiority of DYMBER over DTRT and VMAT indicates utilizing increased DoF to be the key to improve brain and head and neck radiation treatments in future.

Independent Monte-Carlo dose calculation for MLC based CyberKnife radiotherapy.

This work aims to develop, implement and validate a Monte Carlo (MC)-based independent dose calculation (IDC) framework to perform patient-specific quality assurance (QA) for multi-leaf collimator (MLC)-based CyberKnife® (Accuray Inc., Sunnyvale, CA) treatment plans. The IDC framework uses an XML-format treatment plan as exported from the treatment planning system (TPS) and DICOM format patient CT data, an MC beam model using phase spaces, CyberKnife MLC beam modifier transport using the EGS++ class library, a beam sampling and coordinate transformation engine and dose scoring using DOSXYZnrc. The framework is validated against dose profiles and depth dose curves of single beams with varying field sizes in a water tank in units of cGy/Monitor Unit and against a 2D dose distribution of a full prostate treatment plan measured with Gafchromic EBT3 (Ashland Advanced Materials, Bridgewater, NJ) film in a homogeneous water-equivalent slab phantom. The film measurement is compared to IDC results by gamma analysis using 2% (global)/2 mm criteria. Further, the dose distribution of the clinical treatment plan in the patient CT is compared to TPS calculation by gamma analysis using the same criteria. Dose profiles from IDC calculation in a homogeneous water phantom agree within 2.3% of the global max dose or 1 mm distance to agreement to measurements for all except the smallest field size. Comparing the film measurement to calculated dose, 99.9% of all voxels pass gamma analysis, comparing dose calculated by the IDC framework to TPS calculated dose for the clinical prostate plan shows 99.0% passing rate. IDC calculated dose is found to be up to 5.6% lower than dose calculated by the TPS in this case near metal fiducial markers. An MC-based modular IDC framework was successfully developed, implemented and validated against measurements and is now available to perform patient-specific QA by IDC.

Simultaneous optimization of photons and electrons for mixed beam radiotherapy.

The aim of this work is to develop and investigate an inverse treatment planning process (TPP) for mixed beam radiotherapy (MBRT) capable of performing simultaneous optimization of photon and electron apertures. A simulated annealing based direct aperture optimization (DAO) is implemented to perform simultaneous optimization of photon and electron apertures, both shaped with the photon multileaf collimator (pMLC). Validated beam models are used as input for Monte Carlo dose calculations. Consideration of photon pMLC transmission during DAO and a weight re-optimization of the apertures after deliverable dose calculation are utilized to efficiently reduce the differences between optimized and deliverable dose distributions. The TPP for MBRT is evaluated for an academic situation with a superficial and an enlarged PTV in the depth, a left chest wall case including the internal mammary chain and a squamous cell carcinoma case. Deliverable dose distributions of MBRT plans are compared to those of modulated electron radiotherapy (MERT), photon IMRT and if available to those of clinical VMAT plans. The generated MBRT plans dosimetrically outperform the MERT, photon IMRT and VMAT plans for all investigated situations. For the clinical cases of the left chest wall and the squamous cell carcinoma, the MBRT plans cover the PTV similarly or more homogeneously than the VMAT plans, while OARs are spared considerably better with average reductions of the mean dose to parallel OARs and D 2% to serial OARs by 54% and 26%, respectively. Moreover, the low dose bath expressed as V 10% to normal tissue is substantially reduced by up to 45% compared to the VMAT plans. A TPP for MBRT including simultaneous optimization is successfully implemented and the dosimetric superiority of MBRT plans over MERT, photon IMRT and VMAT plans is demonstrated for academic and clinical situations including superficial targets with and without deep-seated part.

Assessing dose rate distributions in VMAT plans.

Dose rate is an essential factor in radiobiology. As modern radiotherapy delivery techniques such as volumetric modulated arc therapy (VMAT) introduce dynamic modulation of the dose rate, it is important to assess the changes in dose rate. Both the rate of monitor units per minute (MU rate) and collimation are varied over the course of a fraction, leading to different dose rates in every voxel of the calculation volume at any point in time during dose delivery. Given the radiotherapy plan and machine specific limitations, a VMAT treatment plan can be split into arc sectors between Digital Imaging and Communications in Medicine control points (CPs) of constant and known MU rate. By calculating dose distributions in each of these arc sectors independently and multiplying them with the MU rate, the dose rate in every single voxel at every time point during the fraction can be calculated. Independently calculated and then summed dose distributions per arc sector were compared to the whole arc dose calculation for validation. Dose measurements and video analysis were performed to validate the calculated datasets. A clinical head and neck, cranial and liver case were analyzed using the tool developed. Measurement validation of synthetic test cases showed linac agreement to precalculated arc sector times within ±0.4 s and doses ±0.1 MU (one standard deviation). Two methods for the visualization of dose rate datasets were developed: the first method plots a two-dimensional (2D) histogram of the number of voxels receiving a given dose rate over the course of the arc treatment delivery. In similarity to treatment planning system display of dose, the second method displays the dose rate as color wash on top of the corresponding computed tomography image, allowing the user to scroll through the variation over time. Examining clinical cases showed dose rates spread over a continuous spectrum, with mean dose rates hardly exceeding 100 cGy min(-1) for conventional fractionation. A tool to analyze dose rate distributions in VMAT plans with sub-second accuracy was successfully developed and validated. Dose rates encountered in clinical VMAT test cases show a continuous spectrum with a mean less than or near 100 cGy min(-1) for conventional fractionation.

Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation.

UNLABELLED: Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2-M cell-cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1-S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1-S and G2-M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wild-type p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell-cycle distribution profiling indicates constantly lower G1 and higher G2-M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared with the parental counterpart. IMPLICATIONS: The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, as p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA-damaging agents for MET-positive/p53-negative tumors.

Beamlet based direct aperture optimization for MERT using a photon MLC.

PURPOSE: A beamlet based direct aperture optimization (DAO) for modulated electron radiotherapy (MERT) using photon multileaf collimator (pMLC) shaped electron fields is developed and investigated. METHODS: The Swiss Monte Carlo Plan (SMCP) allows the calculation of dose distributions for pMLC shaped electron beams. SMCP is interfaced with the Eclipse TPS (Varian Medical Systems, Palo Alto, CA) which can thus be included into the inverse treatment planning process for MERT. This process starts with the import of a CT-scan into Eclipse, the contouring of the target and the organs at risk (OARs), and the choice of the initial electron beam directions. For each electron beam, the number of apertures, their energy, and initial shape are defined. Furthermore, the DAO requires dose-volume constraints for the structures contoured. In order to carry out the DAO efficiently, the initial electron beams are divided into a grid of beamlets. For each of those, the dose distribution is precalculated using a modified electron beam model, resulting in a dose list for each beamlet and energy. Then the DAO is carried out, leading to a set of optimal apertures and corresponding weights. These optimal apertures are now converted into pMLC shaped segments and the dose calculation for each segment is performed. For these dose distributions, a weight optimization process is launched in order to minimize the differences between the dose distribution using the optimal apertures and the pMLC segments. Finally, a deliverable dose distribution for the MERT plan is obtained and loaded back into Eclipse for evaluation. For an idealized water phantom geometry, a MERT treatment plan is created and compared to the plan obtained using a previously developed forward planning strategy. Further, MERT treatment plans for three clinical situations (breast, chest wall, and parotid metastasis of a squamous cell skin carcinoma) are created using the developed inverse planning strategy. The MERT plans are compared to clinical standard treatment plans using photon beams and the differences between the optimal and the deliverable dose distributions are determined. RESULTS: For the idealized water phantom geometry, the inversely optimized MERT plan is able to obtain the same PTV coverage, but with an improved OAR sparing compared to the forwardly optimized plan. Regarding the right-sided breast case, the MERT plan is able to reduce the lung volume receiving more than 30% of the prescribed dose and the mean lung dose compared to the standard plan. However, the standard plan leads to a better homogeneity within the CTV. The results for the left-sided thorax wall are similar but also the dose to the heart is reduced comparing MERT to the standard treatment plan. For the parotid case, MERT leads to lower doses for almost all OARs but to a less homogeneous dose distribution for the PTV when compared to a standard plan. For all cases, the weight optimization successfully minimized the differences between the optimal and the deliverable dose distribution. CONCLUSIONS: A beamlet based DAO using multiple beam angles is implemented and successfully tested for an idealized water phantom geometry and clinical situations.

Forward treatment planning for modulated electron radiotherapy (MERT) employing Monte Carlo methods.

PURPOSE: This paper describes the development of a forward planning process for modulated electron radiotherapy (MERT). The approach is based on a previously developed electron beam model used to calculate dose distributions of electron beams shaped by a photon multi leaf collimator (pMLC). METHODS: As the electron beam model has already been implemented into the Swiss Monte Carlo Plan environment, the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) can be included in the planning process for MERT. In a first step, CT data are imported into Eclipse and a pMLC shaped electron beam is set up. This initial electron beam is then divided into segments, with the electron energy in each segment chosen according to the distal depth of the planning target volume (PTV) in beam direction. In order to improve the homogeneity of the dose distribution in the PTV, a feathering process (Gaussian edge feathering) is launched, which results in a number of feathered segments. For each of these segments a dose calculation is performed employing the in-house developed electron beam model along with the macro Monte Carlo dose calculation algorithm. Finally, an automated weight optimization of all segments is carried out and the total dose distribution is read back into Eclipse for display and evaluation. One academic and two clinical situations are investigated for possible benefits of MERT treatment compared to standard treatments performed in our clinics and treatment with a bolus electron conformal (BolusECT) method. RESULTS: The MERT treatment plan of the academic case was superior to the standard single segment electron treatment plan in terms of organs at risk (OAR) sparing. Further, a comparison between an unfeathered and a feathered MERT plan showed better PTV coverage and homogeneity for the feathered plan, with V95% increased from 90% to 96% and V107% decreased from 8% to nearly 0%. For a clinical breast boost irradiation, the MERT plan led to a similar homogeneity in the PTV compared to the standard treatment plan while the mean body dose was lower for the MERT plan. Regarding the second clinical case, a whole breast treatment, MERT resulted in a reduction of the lung volume receiving more than 45% of the prescribed dose when compared to the standard plan. On the other hand, the MERT plan leads to a larger low-dose lung volume and a degraded dose homogeneity in the PTV. For the clinical cases evaluated in this work, treatment plans using the BolusECT technique resulted in a more homogenous PTV and CTV coverage but higher doses to the OARs than the MERT plans. CONCLUSIONS: MERT treatments were successfully planned for phantom and clinical cases, applying a newly developed intuitive and efficient forward planning strategy that employs a MC based electron beam model for pMLC shaped electron beams. It is shown that MERT can lead to a dose reduction in OARs compared to other methods. The process of feathering MERT segments results in an improvement of the dose homogeneity in the PTV.

Adjuvant therapy after resection of brain metastases. Frameless image-guided LINAC-based radiosurgery and stereotactic hypofractionated radiotherapy.

BACKGROUND: Tumor bed stereotactic radiosurgery (SRS) after resection of brain metastases is a new strategy to delay or avoid whole-brain irradiation (WBRT) and its associated toxicities. This retrospective study analyzes results of frameless image-guided linear accelerator (LINAC)-based SRS and stereotactic hypofractionated radiotherapy (SHRT) as adjuvant treatment without WBRT. MATERIALS AND METHODS: Between March 2009 and February 2012, 44 resection cavities in 42 patients were treated with SRS (23 cavities) or SHRT (21 cavities). All treatments were delivered using a stereotactic LINAC. All cavities were expanded by ≥ 2 mm in all directions to create the clinical target volume (CTV). RESULTS: The median planning target volume (PTV) for SRS was 11.1 cm(3). The median dose prescribed to the PTV margin for SRS was 17 Gy. Median PTV for SHRT was 22.3 cm(3). The fractionation schemes applied were: 4 fractions of 6 Gy (5 patients), 6 fractions of 4 Gy (6 patients) and 10 fractions of 4 Gy (10 patients). Median follow-up was 9.6 months. Local control (LC) rates after 6 and 12 months were 91 and 77 %, respectively. No statistically significant differences in LC rates between SRS and SHRT treatments were observed. Distant brain control (DBC) rates at 6 and 12 months were 61 and 33 %, respectively. Overall survival (OS) at 6 and 12 months was 87 and 63.5 %, respectively, with a median OS of 15.9 months. One patient treated by SRS showed symptoms of radionecrosis, which was confirmed histologically. CONCLUSION: Frameless image-guided LINAC-based adjuvant SRS and SHRT are effective and well tolerated local treatment strategies after resection of brain metastases in patients with oligometastatic disease.