Gary Goozee

Absence of atm truncations in patients with severe acute radiation reactions

PURPOSE Severe acute toxicity limits the effective use of radiotherapy in patients who are radiosensitive, and it is not usually possible to identify these radiohypersensitive (R-H) individuals before treatment commences. Five such R-H patients were detected over a 3-year period. We undertook this study to determine whether the severe acute radiohypersensitivity of these five individuals showed any correlation with cellular and molecular parameters known to be abnormal in radiosensitivity-related syndromes such as ataxia-telangiectasia (A-T). METHODS AND MATERIALS Lymphoblastoid cells were isolated from fresh blood from the 5 R-H individuals who had previously demonstrated clinical R-H at least 9 months prior to sampling. Lymphoblastoid cell lines (LCLs) were established to determine the extent of postradiation chromosomal aberrations, cell cycle delay, cell proliferation, and tumor suppressor p53 protein stabilization. The polymerase chain reaction (PCR) and protein truncation (PTT) assays were used to test for the possibility of mutations in the gene mutated in A-T, termed ATM. RESULTS LCLs derived from R-H subjects retained a significantly higher degree of radiation-induced chromosomal aberrations when compared to normal control LCLs. p53 stabilization by ionizing radiation appeared normal in all but one R-H subject. There was no evidence of A-T gene truncation mutations in any of the R-H subjects tested. CONCLUSIONS All R-H subjects in this study had their cellular radiosensitivity confirmed by the chromosomal aberration assay. Delayed p53 stabilization at 4 hours postirradiation in one R-H subject suggested that different etiologies may apply in the radiohypersensitivity investigated in this study.

Production of terbium-152 by heavy ion reactions and proton induced spallation.

Terbium-152 (Tb-152) is of potential value as a radiotracer for radiolanthanides in positron emission tomography. We report the production of Tb-152 by heavy ion reactions at the ANU Tandem accelerator, and by the spallation method at the CERN proton accelerator using the on-line ISOLDE separator, obtaining microcurie and millicurie yields, respectively. After purification, a phantom image in PET is obtained which shows the feasibility of using Tb-152 for monitoring the kinetics of Tb-149 and other radiolanthanides. However, the current availability of this radioisotope will be restricted to major nuclear physics research centres.

In vitro testing of the leukaemia monoclonal antibody WM-53 labeled with alpha and beta emitting radioisotopes

We report the preparation and testing of a new alpha emitting radio-immunoconjugate (RIC) against acute myeloid leukaemia (AML) using CD33 positive monoclonal antibody WM-53 (specific for HL-60 cell line). Using cyclic anhydride of diethylenetriaminepentacetic acid (cDTPAa) as chelator, antibody was labeled with 213Bi (alpha), 149Tb (alpha), 153Sm (beta) and 152Tb (positron). In vitro testing showed high labeling efficiency (90-95%) and stability (11-19% leaching) with immunoreactivity virtually the same before and after labeling. DNA synthesis data and MTS cell survival were compared for all RICs. Only the alpha emitter was found to be capable of inhibiting DNA synthesis and had selective cell kill with activity as low as 2-3 microCi. The high stability and outstanding cytotoxicity of the 213Bi conjugate provides the basis for targeted alpha therapy for the control of metastatic and disseminated cancer such as AML.

In vitro and preclinical studies of targeted alpha therapy (TAT) for colorectal cancer.

Effective targeted cancer therapy requires high selectivity and cytotoxicity of the labelled product. We report the preparation and testing of anticolorectal cancer monoclonal antibody c30.6 radioimmunoconjugates (RIC) labelled with alpha‐emitting Bismuth‐213 and positron emitting Terbium‐152 using two chelators, viz. Cyclic dianhydride of diethylenetriaminepentacetic acid (DTPA) and CHX‐A′′ (a DTPA derivative).

Rapid learning in practice: A lung cancer survival decision support system in routine patient care data

Background and purpose A rapid learning approach has been proposed to extract and apply knowledge from routine care data rather than solely relying on clinical trial evidence. To validate this in practice we deployed a previously developed decision support system (DSS) in a typical, busy clinic for non-small cell lung cancer (NSCLC) patients. Material and methods Gender, age, performance status, lung function, lymph node status, tumor volume and survival were extracted without review from clinical data sources for lung cancer patients. With these data the DSS was tested to predict overall survival. Results 3919 lung cancer patients were identified with 159 eligible for inclusion, due to ineligible histology or stage, non-radical dose, missing tumor volume or survival. The DSS successfully identified a good prognosis group and a medium/poor prognosis group (2 year OS 69% vs. 27/30%, p < 0.001). Stage was less discriminatory (2 year OS 47% for stage I–II vs. 36% for stage IIIA–IIIB, p = 0.12) with most good prognosis patients having higher stage disease. The DSS predicted a large absolute overall survival benefit (~40%) for a radical dose compared to a non-radical dose in patients with a good prognosis, while no survival benefit of radical radiotherapy was predicted for patients with a poor prognosis. Conclusions A rapid learning environment is possible with the quality of clinical data sufficient to validate a DSS. It uses patient and tumor features to identify prognostic groups in whom therapy can be individualized based on predicted outcomes. Especially the survival benefit of a radical versus non-radical dose predicted by the DSS for various prognostic groups has clinical relevance, but needs to be prospectively validated.

Independent calculation-based verification of IMRT plans using a 3D dose-calculation engine

Independent monitor unit verification of intensity-modulated radiation therapy (IMRT) plans requires detailed 3-dimensional (3D) dose verification. The aim of this study was to investigate using a 3D dose engine in a second commercial treatment planning system (TPS) for this task, facilitated by in-house software. Our department has XiO and Pinnacle TPSs, both with IMRT planning capability and modeled for an Elekta-Synergy 6MV photon beam. These systems allow the transfer of computed tomography (CT) data and RT structures between them but do not allow IMRT plans to be transferred. To provide this connectivity, an in-house computer programme was developed to convert radiation therapy prescription (RTP) files as generated by many planning systems into either XiO or Pinnacle IMRT file formats. Utilization of the technique and software was assessed by transferring 14 IMRT plans from XiO and Pinnacle onto the other system and performing 3D dose verification. The accuracy of the conversion process was checked by comparing the 3D dose matrices and dose volume histograms (DVHs) of structures for the recalculated plan on the same system. The developed software successfully transferred IMRT plans generated by 1 planning system into the other. Comparison of planning target volume (TV) DVHs for the original and recalculated plans showed good agreement; a maximum difference of 2% in mean dose, - 2.5% in D95, and 2.9% in V95 was observed. Similarly, a DVH comparison of organs at risk showed a maximum difference of +7.7% between the original and recalculated plans for structures in both high- and medium-dose regions. However, for structures in low-dose regions (less than 15% of prescription dose) a difference in mean dose up to +21.1% was observed between XiO and Pinnacle calculations. A dose matrix comparison of original and recalculated plans in XiO and Pinnacle TPSs was performed using gamma analysis with 3%/3mm criteria. The mean and standard deviation of pixels passing gamma tolerance for XiO-generated IMRT plans was 96.1 ± 1.3, 96.6 ± 1.2, and 96.0 ± 1.5 in axial, coronal, and sagittal planes respectively. Corresponding results for Pinnacle-generated IMRT plans were 97.1 ± 1.5, 96.4 ± 1.2, and 96.5 ± 1.3 in axial, coronal, and sagittal planes respectively.

Radiation dose and contralateral breast cancer risk associated with megavoltage cone-beam computed tomographic image verification in breast radiation therapy.

PURPOSE To measure and compare organ doses from a standard tangential breast radiation therapy treatment (50 Gy delivered in 25 fractions) and a megavoltage cone-beam computed tomography (MV-CBCT), taken for weekly image verification, and assess the risk of radiation-induced contralateral breast cancer. METHODS AND MATERIALS Organ doses were measured with thermoluminescent dosimeters placed strategically within a female anthropomorphic phantom. The risk of radiation-induced secondary cancer of the contralateral breast was estimated from these values using excess absolute risk and excess relative risk models. RESULTS The effective dose from a MV-CBCT (8-monitor units) was 35.9 ± 0.2 mSv. Weekly MV-CBCT imaging verification contributes 0.5% and 17% to the total ipsilateral and contralateral breast dose, respectively. For a woman irradiated at age 50 years, the 10-year postirradiation excess relative risk was estimated to be 0.8 and 0.9 for treatment alone and treatment plus weekly MV-CBCT imaging, respectively. The 10-year postirradiation excess absolute risk was estimated to be 4.7 and 5.6 per 10,000 women-years. CONCLUSIONS The increased dose and consequent radiation-induced second cancer risk as calculated by this study introduced by the imaging verification protocols utilizing MV-CBCT in breast radiation therapy must be weighed against the benefits of more accurate treatment. As additional image verification becomes more common, it is important that data be collected in regard to long-term malignancy risk.

Detecting VMAT delivery errors: A study on the sensitivity of the ArcCHECK-3D electronic dosimeter

The sensitivity of the ArcCHECK 3D dosimeter in detecting VMAT delivery errors has been investigated. Dose and leaf positional errors of different magnitudes were introduced to whole arc and individual control points (CPs) of a simple open arc VMAT plan. The error introduced and error free plans were delivered and measured using the ArcCHECK device. The measured doses were compared against the treatment planning system calculated doses using gamma (γ) criteria with 2%/2mm and 3%/3mm tolerance levels. ArcCHECK effectively detected the dose errors resulting from MLC leaf positioning errors in limited CPs and Whole arc. For errors introduced to MU, ArcCHECK effectively detected the MU delivery errors in whole arc but not the MU errors introduced to CPs in integrated dose comparison.

Is a quasi-3D dosimeter better than a 2D dosimeter for Tomotherapy delivery quality assurance?

Delivery quality assurance (DQA) has been performed for each Tomotherapy patient either using ArcCHECK or MatriXX Evolution in our clinic since 2012. ArcCHECK is a quasi-3D dosimeter whereas MatriXX is a 2D detector. A review of DQA results was performed for all patients in the last three years, a total of 221 DQA plans. These DQA plans came from 215 patients with a variety of treatment sites including head-neck, pelvis, and chest wall. The acceptable Gamma pass rate in our clinic is over 95% using 3mm and 3% of maximum planned dose with 10% dose threshold. The mean value and standard deviation of Gamma pass rates were 98.2% ± 1.98(1SD) for MatriXX and 98.5%±1.88 (1SD) for ArcCHECK. A paired t-test was also performed for the groups of patients whose DQA was performed with both the ArcCHECK and MatriXX. No statistical dependence was found in terms of the Gamma pass rate for ArcCHECK and MatriXX. The considered 3D and 2D dosimeters have achieved similar results in performing routine patient-specific DQA for patients treated on a TomoTherapy unit.

Evaluation of 3D Gamma index calculation implemented in two commercial dosimetry systems

3D Gamma index is one of the metrics which have been widely used for clinical routine patient specific quality assurance for IMRT, Tomotherapy and VMAT. The algorithms for calculating the 3D Gamma index using global and local methods implemented in two software tools: PTW- VeriSoft® as a part of OCTIVIUS 4D dosimeter systems and 3DVHTM from Sun Nuclear were assessed. The Gamma index calculated by the two systems was compared with manual calculated for one data set. The Gamma pass rate calculated by the two systems was compared using 3%/3mm, 2%/2mm, 3%/2mm and 2%/3mm for two additional data sets. The Gamma indexes calculated by the two systems were accurate, but Gamma pass rates calculated by the two software tools for same data set with the same dose threshold were different due to the different interpolation of raw dose data by the two systems and different implementation of Gamma index calculation and other modules in the two software tools. The mean difference was -1.3%±3.38 (1SD) with a maximum difference of 11.7%.