Commissioning of a Versa HDTM linear accelerator for three commercial treatment planning systems.

In a mixed-vendor radiation oncology environment, it is advantageous if the department's treatment planning system (TPS) supports the linear accelerators of different vendors. In this publication beam data collection and modeling for the Versa HD linear accelerator in Monaco, Pinnacle, and Eclipse are discussed. In each TPS static field, Intensity-Modulated Radiation Therapy (IMRT) step and shoot, and Volumetric-Modulated Arc Therapy (VMAT) plans for flattened and flattening-filter free photon beams of all available energies were evaluated for field sizes >3 × 3. To compare passing rates, identical beam model validation plans were calculated in each TPS. Eclipse, Monaco, and Pinnacle beam models passed validation measurements in homogeneous materials for a variety of treatment fields, including static, IMRT, and VMAT. In the case of Eclipse, the "dosimetric leaf gap" parameter was found to be critical for passing rates of VMAT plans. The source size parameter plays an important role as well for small fields. In the case of Pinnacle the multileaf collimator offset table needed to be optimized for better VMAT QA results. Each of the investigated treatment planning systems met the criteria to be used clinically in conjunction with Elekta Versa HD linear accelerators. It can be of great advantage to have the option to operate a TPS and linear accelerator from different vendors, as decisions surrounding linear accelerator or TPS purchases are very complicated and not just limited to technical considerations.

Updated risk models demonstrate low risk of symptomatic radionecrosis following stereotactic radiosurgery for brain metastases.

BACKGROUND: Improvements in systemic therapy continue to increase survival for patients with brain metastases. Updated dosimetric models are required to optimize long-term safety of stereotactic radiosurgery (SRS) for this indication. METHODS: Patients at a single institution receiving SRS from December 2011 to December 2014 were retrospectively reviewed. Patients with radiographic progression of at least one lesion, and with at least 6 months of follow-up from the start of SRS were included. Grade 3 necrosis was defined as requiring surgical intervention. This data were combined with two additional published datasets to construct logistic models describing necrosis risk as a function of dose and volume. RESULTS: From our institution, 294 brain metastases across 57 patients in 139 treatment plans met inclusion criteria. Primary histologies included non-small cell lung cancer (n = 19), melanoma (n = 13), breast carcinoma (n = 9), renal cell carcinoma (n = 7), and other (n = 9). Median follow-up from SRS of first cranial metastasis was 21.7 months (range: 6.3-56.6) and median overall survival was 25.6 months (range: 6.5-56.6). There were eight cases of Grade 1-2 and two cases of Grade 3 necrosis. As a useful clinical reference point, 20 cc of total brain receiving a single-fraction equivalent dose ≥14 Gy corresponded to 12.1% risk for Grade 1-3 (P < 0.003) and 3.4% risk for Grade 3 necrosis (P < 0.001). CONCLUSIONS: These results compare favorably with the QUANTEC brain tolerance estimates for radiosurgery, providing optimism for lower toxicity in the modern era. Additional studies are needed to determine dose tolerance parameters across a broad spectrum of patients.

Comparison of treatment planning approaches for spatially fractionated irradiation of deep tumors.

PURPOSE: The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets. METHODS: Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined. RESULTS: The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min). CONCLUSION: Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.

Patterns of Incident Reporting Across Clinical Sites in a Regionally Expanding Academic Radiation Oncology Department.

PURPOSE: We evaluated patterns of event reporting across five clinical locations within an academic radiation oncology department, with the goal of better understanding variability across sites. METHODS AND MATERIALS: We analyzed 1,351 events reported to a departmental incident learning system over 1 calendar year across the five locations with respect to volume of events, event type, process map location of origin and detection, and event reporter. RESULTS: We found marked variability in reporting patterns, including reporting rate, event type, event severity, event location of origin and detection within the departmental process map, and discipline of event reporters. These differences relate both to variability in process and workflow (reflected by frequency of specific workflow events at each site) and in reporting culture (reflected by volume or rate of event reporting, and discipline of event reporter). CONCLUSIONS: These data highlight the variability in reporting culture even within a single department, and therefore the need to tailor and individualize safety and quality programs to the unique clinical site, with the long-term goal of achieving a common culture of safety while supporting unique processes at individual locations. This work also raises concern about extrapolating single-institution incident learning system results without understanding the unique workflow and culture of clinical sites.

68Ga-PSMA-PET/CT imaging of localized primary prostate cancer patients for intensity modulated radiation therapy treatment planning with integrated boost.

PURPOSE: The purpose of our study was to show the feasibility and potential benefits of using 68Ga-PSMA-PET/CT imaging for radiation therapy treatment planning of patients with primary prostate cancer using either integrated boost on the PET-positive volume or localized treatment of the PET-positive volume. The potential gain of such an approach, the improvement of tumor control, and reduction of the dose to organs-at-risk at the same time was analyzed using the QUANTEC biological model. METHODS: Twenty-one prostate cancer patients (70 years average) without previous local therapy received 68Ga-PSMA-PET/CT imaging. Organs-at-risk and standard prostate target volumes were manually defined on the obtained datasets. A PET active volume (PTV_PET) was segmented with a 40% of the maximum activity uptake in the lesion as threshold followed by manual adaption. Five different treatment plan variations were calculated for each patient. Analysis of derived treatment plans was done according to QUANTEC with in-house developed software. Tumor control probability (TCP) and normal tissue complication probability (NTCP) was calculated for all plan variations. RESULTS: Comparing the conventional plans to the plans with integrated boost and plans just treating the PET-positive tumor volume, we found that TCP increased to (95.2 ± 0.5%) for an integrated boost with 75.6 Gy, (98.1 ± 0.3%) for an integrated boost with 80 Gy, (94.7 ± 0.8%) for treatment of PET-positive volume with 75 Gy, and to (99.4 ± 0.1%) for treating PET-positive volume with 95 Gy (all p < 0.0001). For the integrated boost with 80 Gy, a significant increase of the median NTCP of the rectum was found, for all other plans no statistical significant increase in the NTCP neither of the rectum nor the bladder was found. CONCLUSIONS: Our study demonstrates that the use of 68Ga-PSMA-PET/CT image information allows for more individualized prostate treatment planning. TCP values of identified active tumor volumes were increased, while rectum and bladder NTCP values either remained the same or were even lower. However, further studies need to clarify the clinical benefit for the patients applying these techniques.

Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance.

Clinical radiation therapy measurements with a new commercial synthetic single crystal diamond detector.

A commercial version of a synthetic single crystal diamond detector (SCDD) in a Schottky diode configuration was recently released as the new type 60019 microDiamond detector (PTW-Freiburg, Germany). In this study we investigate the dosimetric properties of this detector to independently confirm that findings from the developing group of the SCDDs still hold true for the commercial version of the SCDDs. We further explore if the use of the microDiamond detector can be expanded to high-energy photon beams of up to 15 MV and to large field measure- ments. Measurements were performed with an Elekta Synergy linear accelerator delivering 6, 10, and 15 MV X-rays, as well as 6, 9, 12, 15, and 20 MeV electron beams. The dependence of the microdiamond detector response on absorbed dose after connecting the detector was investigated. Furthermore, the dark current of the diamond detector was observed after irradiation. Results are compared to similar results from measurements with a diamond detector type 60003. Energy dependency was investigated, as well. Photon depth-dose curves were measured for field sizes 3 × 3, 10 × 10, and 30 × 30 cm2. PDDs were measured with the Semiflex type 31010 detector, microLion type 31018 detector, P Diode type 60016, SRS Diode type 60018, and the microDiamond type 60019 detector (all PTW-Freiburg). Photon profiles were measured at a depth of 10 cm. Electron depth-dose curves normalized to the dose maximum were measured with the 14 × 14 cm2 electron cone. PDDs were measured with a Markus chamber type 23343, an E Diode type 60017 and the microDiamond type 60019 detector (all PTW-Freiburg). Profiles were measured with the E Diode and microDiamond at half of D90, D90, D70, and D50 depths and for electron cone sizes of 6 × 6 cm2, 14 × 14 cm2, and 20 × 20 cm2. Within a tol- erance of 0.5% detector response of the investigated detector was stable without any preirradiation. After preirradition with approximately 250 cGy the detector response was stable within 0.1%. A dark current after irradiation was not observed. The microDiamond detector shows no energy dependence in high energy photon or electron dosimetry. Electron PDD measurements with the E Diode and micro- Diamond are in good agreement. However, compared to E Diode measurements, dose values in the bremsstrahlungs region are about 0.5% lower when measured with the microDiamond detector. Markus detector measurements agree with E Diode measurements in the bremsstrahlungs region. For depths larger than dmax, depth-dose curves of photon beams measured with the microDiamond detector are in close agreement to those measured with the microLion detector for small fields and with those measured with a Semiflex 0.125 cc ionization chamber for large fields. Differences are in the range of 0.25% and less. For profile measurements, microDiamond detector measurements agree well with microLion and P Diode measurements in the high-dose region of the profile and the penumbra region. For areas outside the open field, P Diode measurements are about 0.5%-1.0% higher than microDiamond and microLion measurements. Thus it becomes evident that the investigated diamond detector (type 60019) is suitable for a wide range of applications in high-energy photon and electron dosimetry and is interesting for relative, as well as absolute, dosimetry. 

Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma.

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.

Circumferential or sectored beam arrangements for stereotactic body radiation therapy (SBRT) of primary lung tumors: effect on target and normal-structure dose-volume metrics.

To compare 2 beam arrangements, sectored (beam entry over ipsilateral hemithorax) vs circumferential (beam entry over both ipsilateral and contralateral lungs), for static-gantry intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) delivery techniques with respect to target and organs-at-risk (OAR) dose-volume metrics, as well as treatment delivery efficiency. Data from 60 consecutive patients treated using stereotactic body radiation therapy (SBRT) for primary non-small-cell lung cancer (NSCLC) formed the basis of this study. Four treatment plans were generated per data set: IMRT/VMAT plans using sectored (-s) and circumferential (-c) configurations. The prescribed dose (PD) was 60Gy in 5 fractions to 95% of the planning target volume (PTV) (maximum PTV dose ~ 150% PD) for a 6-MV photon beam. Plan conformality, R50 (ratio of volume circumscribed by the 50% isodose line and the PTV), and D2cm (Dmax at a distance ≥2cm beyond the PTV) were evaluated. For lungs, mean doses (mean lung dose [MLD]) and percent V30/V20/V10/V5Gy were assessed. Spinal cord and esophagus Dmax and D5/D50 were computed. Chest wall (CW) Dmax and absolute V30/V20/V10/V5Gy were reported. Sectored SBRT planning resulted in significant decrease in contralateral MLD and V10/V5Gy, as well as contralateral CW Dmax and V10/V5Gy (all p < 0.001). Nominal reductions of Dmax and D5/D50 for the spinal cord with sectored planning did not reach statistical significance for static-gantry IMRT, although VMAT metrics did show a statistically significant decrease (all p < 0.001). The respective measures for esophageal doses were significantly lower with sectored planning (p < 0.001). Despite comparable dose conformality, irrespective of planning configuration, R50 significantly improved with IMRT-s/VMAT-c (p < 0.001/p = 0.008), whereas D2cm significantly improved with VMAT-c (p < 0.001). Plan delivery efficiency improved with sectored technique (p < 0.001); mean monitor unit (MU)/cGy of PD decreased from 5.8 ± 1.9 vs 5.3 ± 1.7 (IMRT) and 2.7 ± 0.4 vs 2.4 ± 0.3 (VMAT). The sectored configuration achieves unambiguous dosimetric advantages over circumferential arrangement in terms of esophageal, contralateral CW, and contralateral lung sparing, in addition to being more efficient at delivery.

Monte Carlo dose calculations in the treatment of a pelvis with implant and comparison with pencil-beam calculations.

In the present paper, dose distribution calculated with the Monte Carlo code EGS4 and with a pencil-beam algorithm are compared for the treatment of a pelvis with an implant. Overestimations of dose values inside the target volume by the pencil-beam algorithm of up to 10% were found, which are attributed to the underestimation of the absorption of photons by the implant. The differences in dose distributions are also expressed by comparing the tumor control probability (TCP) of the Monte Carlo dose calculations with the TCP of the pencil-beam calculations. A TCP reduction of order of 30% was found.

The volume effect of detectors in the dosimetry of small fields used in IMRT.

In this study we investigate the effect of detector size in the dosimetry of small fields and steep dose gradients with a particular emphasis on IMRT measurements. Comparisons of calculated and measured cross-profiles and absolute dose values of IMRT treatment plans are presented. As a consequence of the finite size of the detector that was used for the commissioning of the IMRT tool, local discrepancies of more than 10% are found between calculated cross-profiles of intensity modulated beams and intensity modulated profiles measured with film. Absolute dose measurements of intensity modulated fields with a 0.6 cm3 Farmer chamber show significant differences of more than 6% between calculated and measured dose values at the isocenter of an IMRT treatment plan. Differences of not more than 2% are found in the same experiment for dose values measured with a 0.015 cm3 pinpoint ion chamber. A method to correct for the spatial response of finite-sized detectors and to obtain the "real" penumbra width of cross-profiles from measurements is introduced. Output factor measurements are performed with different detectors and are presented as a function of detector size for a 1 x 1 cm2 field. Because of its high spatial resolution and water equivalence, a diamond detector is found to be suitable as an alternative to other detectors used for small field dosimetry as there are photographic and photochromic film, TLDs, or water-equivalent scintillation detectors.

Comparison of TG-43 dose calculations to pinpoint ion chamber and diamond detector measurements.

Brachytherapy is an area of radiation therapy where the availability of high-resolution detectors with a low energy-dependence is of great importance. The suitability of two detectors is investigated in this study. Measurements in the proximity of an Ir-192 source were performed with a diamond detector type 60003 and a pinpoint chamber type 31006 (both PTW-Freiburg). For comparison, dose values were calculated with the dose calculation formalism recommended by the task group 43 (Nath et al 1995 Med. Phys. 22 209-34).