Evaluating stereotactic accuracy with patient-specific MRI distortion corrections for frame-based radiosurgery.

PURPOSE: This study examines how MRI distortions affect frame-based SRS treatments and assesses the need for clinical distortion corrections. METHODS: The study included 18 patients with 80 total brain targets treated using frame-based radiosurgery. Distortion within patients' MRIs were corrected using Cranial Distortion Correction (CDC) software, which utilizes the patient's CT to alter planning MRIs to reduce inherent intra-cranial distortion. Distortion was evaluated by comparing the original planning target volumes (PTVORIG) to targets contoured on corrected MRIs (PTVCORR). To provide an internal control, targets were also re-contoured on uncorrected (PTVRECON) MRIs. Additional analysis was done to assess if 1 mm expansions to PTVORIG targets would compensate for patient-specific distortions. Changes in target volumes, DICE and JACCARD similarity coefficients, minimum PTV dose (Dmin), dose to 95% of the PTV (D95%), and normal tissue receiving 12 Gy (V12Gy), 10 Gy (V10Gy), and 5 Gy (V5Gy) were calculated and evaluated. Student's t-tests were used to determine if changes in PTVCORR were significantly different than intra-contouring variability quantified by PTVRECON. RESULTS: PTVRECON and PTVCORR relative changes in volume were 6.19% ± 10.95% and 1.48% ± 32.92%. PTVRECON and PTVCORR similarity coefficients were 0.90 ± 0.08 and 0.73 ± 0.16 for DICE and 0.82 ± 0.12 and 0.60 ± 0.18 for JACCARD. PTVRECON and PTVCORR changes in Dmin were -0.88% ± 8.77% and -12.9 ± 17.3%. PTVRECON and PTVCORR changes in D95% were -0.34% ± 5.89 and -8.68% ± 13.21%. The 1 mm expanded PTVORIG targets did not entirely cover 14 of the 80 PTVCORR targets. Normal tissue changes (V12Gy, V10Gy, V5Gy) calculated with PTVRECON were (-0.09% ± 7.39%, -0.38% ± 5.67%, -0.08% ± 2.04%) and PTVCORR were (-2.14% ± 7.34%, -1.42% ± 5.45%, -0.61% ± 1.93%). Except for V10Gy, all PTVCORR changes were significantly different (p < 0.05) than PTVRECON. CONCLUSION: MRIs used for SRS target delineation exhibit notable geometric distortions that may compromise optimal dosimetric accuracy. A uniform 1 mm expansion may result in geometric misses; however, the CDC algorithm provides a feasible solution for rectifying distortions, thereby enhancing treatment precision.

Commissioning and validation of a Monte Carlo algorithm for spine stereotactic radiosurgery.

PURPOSE: A 6FFF Monte Carlo (MC) dose calculation algorithm was commissioned for spine stereotactic radiosurgery (SRS). Model generation, validation, and ensuing model tuning are presented. METHODS: The model was generated using in-air and in-water commissioning measurements of field sizes between 10 and 400 mm2 . Commissioning measurements were compared to simulated water tank MC calculations to validate output factors, percent depth doses (PDDs), profile sizes and penumbras. Previously treated Spine SRS patients were re-optimized with the MC model to achieve clinically acceptable plans. Resulting plans were calculated on the StereoPHAN phantom and subsequently delivered to the microDiamond and SRSMapcheck to verify calculated dose accuracy. Model tuning was performed by adjusting the model's light field offset (LO) distance between physical and radiological positions of the MLCs, to improve field size and StereoPHAN calculation accuracy. Following tuning, plans were generated and delivered to an anthropomorphic 3D-printed spine phantom featuring realistic bone anatomy, to validate heterogeneity corrections. Finally, plans were validated using polymer gel (VIPAR based formulation) measurements. RESULTS: Compared to open field measurements, MC calculated output factors and PDDs were within 2%, profile penumbra widths were within 1 mm, and field sizes were within 0.5 mm. Calculated point dose measurements in the StereoPHAN were within 0.26% ± 0.93% and -0.10% ± 1.37% for targets and spinal canals, respectively. Average SRSMapcheck per-plan pass rates using a 2%/2 mm/10% threshold relative gamma analysis was 99.1% ± 0.89%. Adjusting LOs improved open field and patient-specific dosimetric agreement. Anthropomorphic phantom measurements were within -1.29% ± 1.00% and 0.27% ± 1.36% of MC calculated for the vertebral body (target) and spinal canal, respectively. VIPAR gel measurements confirmed good dosimetric agreement near the target-spine junction. CONCLUSION: Validation of a MC algorithm for simple fields and complex SRS spine deliveries in homogeneous and heterogeneous phantoms has been performed. The MC algorithm has been released for clinical use.

Simultaneous Optimization of Radiation-Imaging Coincidence for a Multi-Energy Linac.

INTRODUCTION: Medical physics guidelines stress the importance of radiation-imaging coincidence, especially for stereotactic treatments. However, multi-energy linear accelerators may only allow a single imaging isocenter. A procedure was developed to simultaneously optimize radiation-imaging isocenter coincidence for all linac photon energies on a Versa HD. MATERIALS AND METHODS: First, the radiation beam center of each energy was adjusted to match the collimator rotation axis using a novel method that combined ion chamber measurements with a modified Winston-Lutz (WL) test using images only at gantry, couch, and collimator angles of 0°. With all energies properly steered, an 8-field WL test was performed to determine average linac isocenter position across all energies, gantry, and collimator angles. Lasers and the kV imaging isocenter were calibrated to the average linac isocenter of all photon energies. Finally, A 12-field WL test consisting of gantry, couch, and collimator rotations was used to adjust the couch rotation axis to the average linac isocenter, thereby minimizing overall radiation-imaging isocentricity of the system. RESULTS: Using this method, the beam centers were calibrated within 0.10 mm of collimator rotation axis, and linac isocenter coincidence was within 0.20 mm for all energies. Couch isocenter coincidence was adjusted within 0.20 mm of average linac isocenter. Average radiation-imaging isocentricity for all energies was 0.89 mm (0.80-0.98 mm) for a single imaging isocenter. CONCLUSION: This work provides a method to adjust radiation-imaging coincidence within 1.0 mm for all energies on Elekta's Versa HD.

Commissioning cranial single-isocenter multi-target radiosurgery for the Versa HD.

PURPOSE: Brainlab's Elements Multiple Brain Mets SRS (MBMS) is a dedicated treatment planning system for single-isocenter multi-target (SIMT) cranial stereotactic radiosurgery (SRS) treatments. The purpose of this study is to present the commissioning experience of MBMS on an Elekta Versa HD. METHODS: MBMS was commissioned for 6 X, 6 FFF, and 10 FFF. Beam data collected included: output factors, percent depth doses (PDDs), diagonal profiles, collimator transmission, and penumbra. Beam data were processed by Brainlab and resulting parameters were entered into the planning system to generate the beam model. Beam model accuracy was verified for simple fields. MBMS plans were created on previously treated cranial SRS patient data sets. Plans were evaluated using Paddick inverse conformity (ICI), gradient indices (GI), and cumulative volume of brain receiving 12 Gy. Dosimetric accuracy of the MBMS plans was verified using microDiamond, Gafchromic film, and SRS Mapcheck measurements of absolute dose and dose profiles for individual targets. Finally, an end-to-end (E2E) test was performed with a MR-CT compatible phantom to validate the accuracy of the simulation-to-delivery process. RESULTS: For square fields, calculated scatter factors were within 1.0% of measured, PDDs were within 0.5% past dmax, and diagonal profiles were within 0.5% for clinically relevant off-axis distances (<10 cm). MBMS produced plans with ICIs < 1.5 and GIs < 5.0 for targets > 10 mm. Average point doses of the MBMS plans, measured by microDiamond, were within 0.31% of calculated (max 2.84%). Average per-field planar pass rates were 98.0% (95.5% minimum) using a 2%/1 mm/10% threshold relative gamma analysis. E2E point dose measurements were within 1.5% of calculated and Gafchromic film pass rates were 99.6% using a 5%/1 mm/10% threshold gamma analysis. CONCLUSION: The experience presented can be used to aid the commissioning of the Versa HD in the Brainlab MBMS treatment planning system, to produce safe and accurate SIMT cranial SRS treatments.

Technical Note: FLASH radiotherapy monitor chamber signal conditioning.

PURPOSE: Recent studies of ultra-high dose rate FLASH radiotherapy show a substantial reduction of damage to normal tissue cells when compared with conventional radiotherapy. Most, if not all, of these FLASH studies have taken place using either custom research equipment or heavily modified linacs with external dosimetric control. To simplify our preclinical research efforts, we wish to deliver FLASH with a minimally modified linac using the internal dosimetric system. METHODS: To enable the built-in monitor chambers to terminate a FLASH beam, we reversibly modified an Elekta linear accelerator previously fit with a high dose rate electron (HDRE) system to include additional resistance in the signal path from the monitor chambers to the dose control system. To produce the FLASH beam, we altered the energy calibration tables of a decommissioned HDRE beam to functionally produce a photon mode beam current exiting through the electron window of the linac. We then used the machine modifications to assist in beam tuning and to calibrate the monitor chambers for FLASH delivery. We employed a radiochromic film for external dosimetry and preliminary tests of monitor chamber dosimetric stability. RESULTS: We identified attenuation values and distributions that reduced the overall signal from the monitor chambers to the dose control system such that the system could terminate the beam without input from external monitoring circuits. Calibration of the control system resulted in 12 MU per second, constituting roughly 180 Gy at the mylar window. Preliminary tests indicate a linear MU to dose relationship at FLASH dose rates, but we encountered challenges in both dose resolution and repeatability of beam termination. CONCLUSIONS: The addition of attenuation in the control system path from the monitor chambers is fundamentally identical to current HDRE system design and was achieved without significant modification of the accelerator. Preliminary results indicate that current-generation monitor chambers could potentially govern FLASH radiotherapy, but overall beam and monitor chamber stability issues may necessitate machine modifications to achieve desired dosimetric accuracy.

Commissioning of a dedicated commercial Co-60 total body irradiation unit.

We describe the commissioning of the first dedicated commercial total body irradiation (TBI) unit in clinical operation. The Best Theratronics GammaBeam 500 is a Co-60 teletherapy unit with extended field size and imaging capabilities. Radiation safety, mechanical and imaging systems, and radiation output are characterized. Beam data collection, calibration, and external dosimetric validation are described. All radiation safety and mechanical tests satisfied relevant requirements and measured dose distributions meet recommendations of American Association of Physicists in Medicine (AAPM) Report #17. At a typical treatment distance, the dose rate in free space per unit source activity using the thick flattening filter is 1.53 × 10-3 cGy*min-1 *Ci-1 . With a 14,000 Ci source, the resulting dose rate at the midplane of a typical patient is approximately 17 and 30 cGy/min using the thick and thin flattening filters, respectively, using the maximum source to couch distance. The maximum useful field size, defined by the 90% isodose line, at this location is 225 × 78 cm with field flatness within 5% over the central 178 × 73 cm. Measured output agreed with external validation within 0.5%. End-to-end testing was performed in a modified Rando phantom. In-house MATLAB software was developed to calculate patient-specific dose distributions using DOSXYZnrc, and fabricate custom 3D-printed forms for creating patient-specific lung blocks. End-to-end OSLD and diode measurements both with and without lung blocks agreed with Monte Carlo calculated doses to within 5% and in-phantom film measurements validated dose distribution uniformity. Custom lung block transmission measurements agree well with design criteria and provide clinically favorable dose distributions within the lungs. Block placement is easily facilitated using the flat panel imaging system with an exposure time of 0.01 min. In conclusion, a novel dedicated TBI unit has been commissioned and clinically implemented. Its mechanical, dosimetric, and imaging capabilities are suitable to provide state-of-the-art TBI for patients as large as 220 cm in height and 78 cm in width.

Modeling the Agility MLC in the Monaco treatment planning system.

We investigate the relationship between the various parameters in the Monaco MLC model and dose calculation accuracy for an Elekta Agility MLC. The vendor-provided MLC modeling procedure - completed first with external vendor participation and then exclusively in-house - was used in combination with our own procedures to investigate several sets of MLC modeling parameters to determine their effect on dose distributions and point-dose measurements. Simple plans provided in the vendor procedure were used to elucidate specific mechanical characteristics of the MLC, while ten complex treatment plans - five IMRT and five VMAT - created using TG-119-based structure sets were used to test clinical dosimetric effects of particular parameter choices. EDR2 film was used for the vendor fields to give high spatial resolution, while a combination of MapCHECK and ion chambers were used for the in-house TG-119-based proced-ures. The vendor-determined parameter set provided a reasonable starting point for the MLC model and largely delivered acceptable gamma pass rates for clinical plans - including a passing external evaluation using the IROC H&N phantom. However, the vendor model did not provide point-dose accuracy consistent with that seen in other treatment systems at our center. Through further internal testing it was found that there existed many sets of MLC parameters, often at opposite ends of their allowable ranges, that provided similar dosimetric characteristics and good agreement with planar and point-dose measurements. In particular, the leaf offset and tip leakage parameters compensated for one another if adjusted in opposite directions, which provided a level curve of acceptable parameter sets across all plans. Interestingly, gamma pass rates of the plans were less dependent upon parameter choices than point-dose measurements, suggesting that MLC modeling using only gamma evaluation may be generally an insufficient approach. It was also found that exploring all parameters of the very robust MLC model to find the best match to the vendor-provided QA fields can reduce the pass rates of the TG-119-based clinical distributions as compared to simpler models. A wide variety of parameter sets produced MLC models capable of meeting RPC passing criteria for their H&N IMRT phantom. The most accurate models were achievable using a combination of vendor-provided and in-house procedures. The potential existed for an over-modeling of the Agility MLC in an effort to obtain the fine structure of certain quality assurance fields, which led to a reduction in agreement between calculation and measurement of more typical clinical dose distributions.

Evaluation of second-line and subsequent targeted therapies in metastatic renal cell cancer (mRCC) patients treated with first-line cediranib.

INTRODUCTION: Pivotal phase III trials have positioned angiogenesis inhibitors as first-line therapy for the management of most advanced or metastatic renal cell carcinomas (mRCC). Approaches to second-line therapy, however, remain more controversial with respect to drug selection and drug sequencing. METHODS: In this study we evaluated mRCC patients who were initially treated on the first-line National Cancer Institute (NCI) trial with the highly potent vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), cediranib, to determine the efficacy and tolerability of subsequent therapies. RESULTS: Twenty-eight (65.1%) of the 43 patients enrolled on the first-line cediranib trial were known to receive second-line therapy, most commonly sunitinib (n = 21), with 4 (14%), 2 (7%) and 1 (3%) patients receiving temsirolimus, sorafenib, and interleukin, respectively. Of these, 14 (50%) went on to have 3 or more lines of therapy. The progression-free survival (PFS) proportion (PFS) at 1 year from starting second line was 30% (14.5%-47.9%). Longer duration of first-line cediranib treatment was modestly associated with longer duration of second-line treatment (Spearman rho 0.26). Patients who discontinued cediranib for toxicity were less likely to receive second-line sunitinib. CONCLUSION: In this real world evaluation, sequential use of TKIs for the management of mRCC was common. PFS with sequential TKIs was similar to observed and published results for any second-line therapy. Prior toxicity affected treatment patterns and the frequent use of at least 3 lines of therapy underscores the need for prospective sequencing trials in this disease.

Commissioning of intensity modulated neutron radiotherapy (IMNRT).

PURPOSE: Intensity modulated neutron radiotherapy (IMNRT) has been developed using inhouse treatment planning and delivery systems at the Karmanos Cancer Center∕Wayne State University Fast Neutron Therapy facility. The process of commissioning IMNRT for clinical use is presented here. Results of commissioning tests are provided including validation measurements using representative patient plans as well as those from the TG-119 test suite. METHODS: IMNRT plans were created using the Varian Eclipse optimization algorithm and an inhouse planning system for calculation of neutron dose distributions. Tissue equivalent ionization chambers and an ionization chamber array were used for point dose and planar dose distribution comparisons with calculated values. Validation plans were delivered to water and virtual water phantoms using TG-119 measurement points and evaluation techniques. Photon and neutron doses were evaluated both inside and outside the target volume for a typical IMNRT plan to determine effects of intensity modulation on the photon dose component. Monitor unit linearity and effects of beam current and gantry angle on output were investigated, and an independent validation of neutron dosimetry was obtained. RESULTS: While IMNRT plan quality is superior to conventional fast neutron therapy plans for clinical sites such as prostate and head and neck, it is inferior to photon IMRT for most TG-119 planning goals, particularly for complex cases. This results significantly from current limitations on the number of segments. Measured and calculated doses for 11 representative plans (six prostate∕five head and neck) agreed to within -0.8 ± 1.4% and 5.0 ± 6.0% within and outside the target, respectively. Nearly all (22∕24) ion chamber point measurements in the two phantom arrangements were within the respective confidence intervals for the quantity [(measured-planned)∕prescription dose] derived in TG-119. Mean differences for all measurements were 0.5% (max = 7.0%) and 1.4% (max = 4.1%) in water and virtual water, respectively. The mean gamma pass rate for all cases was 92.8% (min = 88.6%). These pass rates are lower than typically achieved with photon IMRT, warranting development of a planar dosimetry system designed specifically for IMNRT and∕or the improvement of neutron beam modeling in the penumbral region. The fractional photon dose component did not change significantly in a typical IMNRT plan versus a conventional fast neutron therapy plan, and IMNRT delivery is not expected to significantly alter the RBE. All other commissioning results were considered satisfactory for clinical implementation of IMNRT, including the external neutron dose validation, which agreed with the predicted neutron dose to within 1%. CONCLUSIONS: IMNRT has been successfully commissioned for clinical use. While current plan quality is inferior to photon IMRT, it is superior to conventional fast neutron therapy. Ion chamber validation results for IMNRT commissioning are also comparable to those typically achieved with photon IMRT. Gamma pass rates for planar dose distributions are lower than typically observed for photon IMRT but may be improved with improved planar dosimetry equipment and beam modeling techniques. In the meantime, patient-specific quality assurance measurements should rely more heavily on point dose measurements with tissue equivalent ionization chambers. No significant technical impediments are anticipated in the clinical implementation of IMNRT as described here.

A phase II study of cediranib (AZD 2171) in treatment naive patients with progressive unresectable recurrent or metastatic renal cell carcinoma. A trial of the PMH phase 2 consortium.

BACKGROUND: Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. METHODS: Eligible patients who had no prior systemic therapy received cediranib 45 mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD) ≥ 4 months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. RESULTS: Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44-83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38 %) partial responses (95 % CI: 23-55 %); 18 stable disease (SD) for a clinical benefit rate of 33/39 = 85 % (95 % CI: 69-94 %) and 6 progressive disease. Median PFS was 8.9 months (95 % CI: 5.1-12.9); and median OS was 28.6 months (95 % CI: 18.2-37.3 months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. CONCLUSIONS: Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30 mg daily appears warranted.