Single isocenter HyperArc treatment of multiple intracranial metastases: Targeting accuracy.

PURPOSE/OBJECTIVES: (A) To examine the alignment accuracy of CBCT guidance for brain metastases with off centered isocenters, (B) to test dose delivery and targeting accuracy for single isocenter treatments with multiple brain metastases. We report the results of the end-to-end test for Truebeam stereotactic radiosurgery (SRS). MATERIALS/METHODS: An anthropomorphic CT head phantom was drilled with five MOSFET inserts and two PTW Pinpoint chamber inserts. The phantom was simulated, planned, and delivered. For the purpose of comparing the accuracy of alignment, CBCTs were acquired with the isocenter centered and offset superiorly 8 cm, inferiorly 8 cm, anteriorly 7 cm, posteriorly 7 cm, and right 5 cm. There were six degrees of freedom corrections applied to the plans, as well as intentional rotational and translational errors for dose comparisons. Dose accuracy checks were performed with MOSFET and PTW Pinpoint chamber, and targeting accuracy was assessed with GafChromic films. RESULT: (A) Compared to centered CBCT, off-centered CBCT scan showed some alignment errors, with a maximum difference of 0.6-degree pitch and 0.9 mm translation when the phantom was placed 8 cm inferior off center. (B) For the single isocenter plan, measured doses of the five MOSFET were 95%-100% of the planned dose, whereas the multiple isocenter plans were 96%-100%. With intentional setup errors of 1-degree pitch, doses were 97.1%-100.4% compared to the perfect setup. The same was found for the two pinpoint chamber readings with 1-degree rotation and 1 mm translation. (C) Targeting accuracy for targets at the isocenter is 0.67 mm, within the machine specification of 0.75 mm. Targeting accuracy for isocenters 6-12 cm away from the target is in the range 0.67-1.18 mm. CONCLUSION: (A) Single isocenter HyperArc treatments for multiple brain metastases are feasible and targeting accuracy is clinically acceptable. (B) The vertex in a cranial scan is very important for proper alignment.

Portal dosimetry correction method for validation of single isocenter VMAT plans for multiple brain metastases.

Portal dosimetry is one option for verification of volumetric-modulated arc therapy (VMAT) planning for multiple brain metastases. However, due to the changing response of the portal imager with photon beam energy, the dose transmitted through closed multileaf collimator (MLC) leaves or narrow MLC gaps may be underestimated by the imager. We present a simple method for correcting for these effects that may be implemented within the Eclipse treatment planning system. We recalculated the predicted portal dose with and without this correction for 20 multiple brain met VMAT plans. Before the correction, 3/20 composite plan fields passed our standard quality assurance (QA) criteria (54/80 individual fields); the average gamma passing rate for the composite plans was 76.9 ± 16.6%, and the average gamma value across the composite plans was 0.67 ± 0.23. After correction, 20/20 composite plan fields passed the QA criteria (80/80 individual fields); the average gamma passing rate for composite plans was 99.2 ± 1.4%, the average gamma value across the composite plans was 0.33 ± 0.90. A measure of plan complexity, the average leaf pair opening could be correlated to the gamma analysis results for the uncorrected plans but not for the corrected plans.

Clinical implementation and evaluation of the Acuros dose calculation algorithm.

PURPOSE: The main aim of this study is to validate the Acuros XB dose calculation algorithm for a Varian Clinac iX linac in our clinics, and subsequently compare it with the wildely used AAA algorithm. METHODS AND MATERIALS: The source models for both Acuros XB and AAA were configured by importing the same measured beam data into Eclipse treatment planning system. Both algorithms were validated by comparing calculated dose with measured dose on a homogeneous water phantom for field sizes ranging from 6 cm × 6 cm to 40 cm × 40 cm. Central axis and off-axis points with different depths were chosen for the comparison. In addition, the accuracy of Acuros was evaluated for wedge fields with wedge angles from 15 to 60°. Similarly, variable field sizes for an inhomogeneous phantom were chosen to validate the Acuros algorithm. In addition, doses calculated by Acuros and AAA at the center of lung equivalent tissue from three different VMAT plans were compared to the ion chamber measured doses in QUASAR phantom, and the calculated dose distributions by the two algorithms and their differences on patients were compared. Computation time on VMAT plans was also evaluated for Acuros and AAA. Differences between dose-to-water (calculated by AAA and Acuros XB) and dose-to-medium (calculated by Acuros XB) on patient plans were compared and evaluated. RESULTS: For open 6 MV photon beams on the homogeneous water phantom, both Acuros XB and AAA calculations were within 1% of measurements. For 23 MV photon beams, the calculated doses were within 1.5% of measured doses for Acuros XB and 2% for AAA. Testing on the inhomogeneous phantom demonstrated that AAA overestimated doses by up to 8.96% at a point close to lung/solid water interface, while Acuros XB reduced that to 1.64%. The test on QUASAR phantom showed that Acuros achieved better agreement in lung equivalent tissue while AAA underestimated dose for all VMAT plans by up to 2.7%. Acuros XB computation time was about three times faster than AAA for VMAT plans, and computation time for other plans will be discussed at the end. Maximum difference between dose calculated by AAA and dose-to-medium by Acuros XB (Acuros_Dm,m ) was 4.3% on patient plans at the isocenter, and maximum difference between D100 calculated by AAA and by Acuros_Dm,m was 11.3%. When calculating the maximum dose to spinal cord on patient plans, differences between dose calculated by AAA and Acuros_Dm,m were more than 3%. CONCLUSION: Compared with AAA, Acuros XB improves accuracy in the presence of inhomogeneity, and also significantly reduces computation time for VMAT plans. Dose differences between AAA and Acuros_Dw,m were generally less than the dose differences between AAA and Acuros_Dm,m . Clinical practitioners should consider making Acuros XB available in clinics, however, further investigation and clarification is needed about which dose reporting mode (dose-to-water or dose-to-medium) should be used in clinics.

Dosimetric parameters related to occurrence of distant metastases and regional nodal relapse after SBRT for early-stage non-small cell lung cancer.

PURPOSE: Previous studies have suggested that the dose immediately outside the PTV may impact the incidence of distant metastases after stereotactic body radiation therapy (SBRT) for patients with early-stage non-small cell lung cancer (NSCLC). In particular, Diamant et al. [1,2] reported a correlation between the mean EQD2 of a 30 mm shell around the PTV and both local control and the rate of distant metastases. In this study, we assess this parameter and others in a series of patients with radiographically presumed or biopsy-proven early-stage NSCLC treated at our institution with stereotactic body radiotherapy (SBRT) between 2017 and 2019. MATERIALS/METHODS: We reviewed the dosimetry, local control, regional nodal relapse, and rate of distant metastases for 304 patients with 325 lesions treated with SBRT at our institution. Dosimetric parameters investigated include the prescribed dose, minimum and mean doses to the PTV, conformity index, and the mean EQD2 to a 30 mm shell around the PTV. Time to each event was defined from date of last fraction of SBRT to date of event, with event-free patients censored at last radiographic follow-up. Univariate (UVA) Cox regression analysis was performed on the collected parameters to assess for correlation with regional nodal relapse and rate of distant metastases. RESULTS: There was no significant correlation between the mean EQD2 dose to a 30 mm shell around the PTV and the rate of distant metastases. On UVA Cox proportional hazards analysis, positive predictors of reduced incidence of distant metastases were PTV <22 cc (vs. ≥22 cc, p = 0.01) and GTV <10 cc (vs. ≥10 cc, p < 0.01), with GTV <10 cc also being a positive predictor of reduced incidence of regional nodal relapse (p < 0.01). In the subset of patients treated with 4-5 fractions, mean EQD2 dose to the 30 mm shell around the PTV ≥21 Gy was associated with increased incidence of distant metastases (HR 2.42, 95% CI 1.06-5.53, p = 0.04), differing from prior data from Diamant et al. CONCLUSIONS: We did not observe a correlation between the rate of distant metastases and dose outside the PTV, as reported by other groups; rather, we noted an opposite trend in patients treated with 4-5 fractions. Our data show additional correlations between distant metastases and tumor size.

Which Dose Specification Should Be Used for NRG Radiation Therapy Trials: Dose-to-Medium or Dose-to-Water?

PURPOSE: To compare the doses calculated by the Analytical Anisotropic Algorithm (AAA), Acuros dose-to-medium, and Acuros dose-to-water for the patients with lung cancer treated at our institution and show that further investigation and clarification are needed about what dose specifications should be used for NRG clinical trials. METHODS AND MATERIALS: Twenty-one patients with lung cancer who previously received intensity modulated radiation therapy or volumetric modulated arc therapy-based treatments at our institution were analyzed by recalculating their plans for each one with the AAA algorithm (reviewed and approved by our radiation oncologists) and with both reporting modes of the Acuros algorithm. All plans used the same monitor units as the original approved plan and a 2.5-mm grid size. For each patient, D100 of clinical target volume (CTV) and CTV coverage ratios in each plan were compared, and dose distributions and dose-volume histograms calculated by AAA, Acuros dose-to-water (Dw,m), and Acuros dose-to-medium (Dm,m) were compared as well. RESULTS: Differences between CTV D100 calculated by AAA and Acuros Dm,m were larger than the differences between AAA and Acuros XB Dw,m for all patients. When D100 of CTV was evaluated, the largest difference between AAA and Acuros Dm,m was 14.12% and between AAA and Acuros XB Dw,m was 3.68%. The average differences between the CTV D100 calculated by AAA and Acuros Dm,m was 5.39%. Coverage ratio between Acuros Dm,m and AAA ranges from 51.08% to 100% with an average of 91.32%; coverage ratio between Acuros Dw,m and AAA ranges from 87.2% to 100.41% with average of 98.94%; coverage ratio between Acuros Dm,m and Acuros Dw,m ranges from 58.58% to 100% with an average of 92.03%. CONCLUSIONS: The present study shows large and systematic differences in doses calculated by AAA and Acuros Dm,m. Therefore, further investigation and clarification are needed about which dose reporting mode should be used.

Application of TG-100 risk analysis methods to the acceptance testing and commissioning process of a Halcyon linear accelerator.

PURPOSE: A new type of linear accelerator (linac) was recently introduced into the market by a major manufacturer. Our institution is one of the early users of this preassembled and preconfigured dual-layer multileaf collimator (MLC), ring-gantry linac - Halcyon™ (1st version). We performed a set of full acceptance testing and commissioning (ATC) measurements for three Halcyon machines and compared the measured data with the standard beam model provided by the manufacturer. The ATC measurements were performed following the guidelines given in different AAPM protocols as well as guidelines provided by the manufacturer. The purpose of the present work was to perform a risk assessment of the ATC process for this new type of linac and investigate whether the results obtained from this analysis could potentially be used as a guideline for improving the design features of this type of linac. METHODS: AAPM's TG100 risk assessment methodology was applied to the ATC process. The acceptance testing process relied heavily on the use of a manufacturer-supplied phantom and the automated analysis of electronic portal imaging device (EPID) images. For the commissioning process, a conventional measurement setup and process (e.g., use of water tank for scanning) was largely used. ATC was performed using guidelines recommended in various AAPM protocols (e.g., TG-106, TG-51) as well as guidelines provided by the manufacturer. Six medical physicists were involved in this study. Process maps, process steps, and failure modes (FMs) were generated for the ATC procedures. Failure modes and effects analysis (FMEA) were performed following the guidelines given in AAPM TG-100 protocol. The top 5 and top 10 highest-ranked FMs were identified for the acceptance and commissioning procedures, respectively. Quality control measures were suggested to mitigate these FMs. RESULTS: A total of 38 steps and 88 FMs were identified for the entire ATC process. Fourteen steps and 34 FMs arose from acceptance testing. The top 5 FMs that were identified could potentially be mitigated by the manufacturer. For commissioning, a total of 24 steps and 54 potential FMs were identified. The use of separate measurement tools that are not machine-integrated has been identified as a cause for the higher number of steps and FMs generated from the conventional ATC approach. More than half of the quality control measures recommended for both acceptance and commissioning could potentially be incorporated by the manufacturer in the design of the Halcyon machine. CONCLUSION: This paper presents the results of FMEA and quality control measures to mitigate the FMs for the ATC process for Halcyon machine. Unique FMs that result from the differences in the ATC guidelines provided by the vendor and current conventional protocols, and the challenges of performing the ATC due to the new linac features and ring-gantry design were highlighted for the first time. The FMs identified in the present work along with the suggested quality control measures, could potentially be used to improve the design features of future ring-gantry type of linacs that are likely to be preassembled, preconfigured, and heavily reliant on automation and image guidance.

A dosimetric evaluation of the IAEA-AAPM TRS483 code of practice for dosimetry of small static fields used in conventional linac beams and comparison with IAEA TRS-398, AAPM TG51, and TG51 Addendum protocols.

PURPOSE: The International Atomic Energy Agency (IAEA) and the American Association of Physicists in Medicine (AAPM) have jointly published a new code of practice (CoP), TRS483, for the dosimetry of small static photon fields used in external beam radiotherapy. It gave recommendations on how to perform reference dosimetry in nonstandard machine-specific reference (msr) fields and measure field output factors in small fields. The purpose of this work was to perform a dosimetric evaluation of the recommendations given in this CoP. METHODS: All measurements were done in a Varian TrueBeam™ STx linear accelerator. Five ionization chambers were used for beam quality measurements, four Farmer type ionization chambers for performing reference dosimetry and two diodes for performing field output factor measurements. Field output factor measurements were done for fourteen field sizes (ranging from 0.5 cm × 0.5 cm to 10 cm × 10 cm). Beam energies used were: 6 MV WFF, 6 MV FFF, 10 MV WFF, and 10 MV FFF. Where appropriate, results from this study were compared with those obtained from the recommendations given in the IAEA TRS398 CoP, AAPM TG51 and TG51 Addendum protocols. RESULTS: Beam quality measurements show that for all beam energies and for equivalent square msr field sizes ranging from 4 cm × 4 cm to 10 cm × 10 cm, agreement between calculated and measured values of TPR20,10 (10) was within 0.6%. When %dd(10,10)X was used as beam quality specifier, the agreement was found to be within 0.8%. Absorbed dose to water per unit monitor unit at the depth of maximum dose zmax in a beam of quality Q, Dw,Qzmax/MU, was determined using both %dd(10,10)X and TPR20,10 (10) as beam quality specifiers. Measured ratios of Dw,Q (zmax )/MU, determined using the two approaches, ranged between 0.999 and 1.000 for all the beam energies investigated. Comparison with TRS398, TG51 and TG51 addendum protocols show that depending on beam energy, the mean values of the ratios TRS398/TRS483, TG51/TRS483, and TG51 Addendum/TRS483 of Dw,Q (zmax )/MU determined using both approaches show excellent agreement with TRS398 CoP (to within 0.05%); agreement with TG51 and TG51 addendum was to within 0.3% for all four beam energies investigated. Field output factors, determined using the two methods recommended in the TRS483 CoP, showed excellent agreement between the two methods. For the 1 cm collimator field size, the mean value of the field output factor obtained from an average of the two detectors investigated was found to be 2% lower than the mean value of the uncorrected ratio of readings. CONCLUSION: For beams with and without flattening filters, the values of Dw,Q (zmax )/MU obtained following the new CoP are found to be consistent with those obtained using TRS398, TG51 and TG51 addendum protocols to within 0.3%. Field output factors for small beams can be improved when the correction factors for different detectors included in TRS483 are appropriately incorporated into their dosimetry.

ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation.

DNA-damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between programmed death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non-small cell lung cancer, melanoma, and head and neck squamous cell carcinoma. ATR is a DNA damage-signaling kinase activated at damaged replication forks, and ATR kinase inhibitors potentiate the cytotoxicity of DNA-damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate CD8+ T cell activity in mouse models of Kras-mutant cancer. Mechanistically, AZD6738 blocks radiation-induced PD-L1 upregulation on tumor cells and dramatically decreases the number of tumor-infiltrating Tregs. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.