Martin A. Ebert

A comparison of the gamma index analysis in various commercial IMRT/VMAT QA systems.

PURPOSE To investigate the variability of the global gamma index (γ) analysis in various commercial IMRT/VMAT QA systems and to assess the impact of measurement with low resolution detector arrays on γ. MATERIALS Five commercial QA systems (PTW 2D-Array, Scandidos Delta4, SunNuclear ArcCHECK, Varian EPID, and Gafchromic EBT2 film) were investigated. The response of γ analysis to deliberately introduced errors in pelvis and head & neck IMRT and RapidArc™ plans was evaluated in each system. A theoretical γ was calculated in each commercial QA system software (PTW Verisoft, Delta4 software, SNC Patient, Varian Portal Dosimetry and IBA OmniPro, respectively), using treatment planning system resolution virtual measurements and compared to an independent calculation. Error-induced plans were measured on a linear accelerator and were evaluated against the error-free dose distribution calculated using Varian Eclipse™ in the relevant phantom CT scan. In all cases, global γ was used with a 20% threshold relative to a point selected in a high dose and low gradient region. The γ based on measurement was compared against the theoretical to evaluate the response of each system. RESULTS There was statistically good agreement between the predicted γ based on the virtual measurements from each software (concordance correlation coefficient, ρc>0.92) relative to the independent prediction in all cases. For the actual measured data, the agreement with the predicted γ reduces with tightening passing criteria and the variability between the different systems increases. This indicates that the detector array configuration and resolution have greater impact on the experimental calculation of γ due to under-sampling of the dose distribution, blurring effects, noise, or a combination. CONCLUSIONS It is important to understand the response and limitations of the gamma index analysis combined with the equipment in use. For the same pass-rate criteria, different devices and software combinations exhibit varying levels of agreement with the predicted γ analysis.

Viability of the EUD and TCP concepts as reliable dose indicators

The concept of equivalent uniform dose (EUD) was introduced to provide a method of reporting radiotherapy dose distributions which takes account of the nonlinearity of tissue dose-response, whilst not attempting to make predictions of absolute outcome. The purpose of this investigation was to determine the level of sensitivity of EUD to model parameters for significant variations in dose distribution and consequently the reliability of the factor as a dose-indicator, and to compare EUD with the more familiar index, tumour control probability (TCP). EUD and TCP, derived from the linear-quadratic formalism, were investigated for a test tissue being irradiated non-uniformly. Variations in the parameters of the model (tissue cell characteristics, dose heterogeneity, fractionation parameters) indicated the sensitivity of EUD and TCP to them. For time independent factors--cell density, cell radiosensitivity, radiosensitivity heterogeneity (population averaged) and ratio alpha/beta--EUD was found to vary insignificantly in comparison with TCP, though this is a function of the actual form of the dose distribution under consideration. For fractionated treatments where the mean dose per fraction is varying (due to dosimetric/positioning errors for example), both EUD and TCP showed little variation with the degree of dose non-uniformity. For other time dependent factors, fractionation rate and cell repopulation times, TCP again showed significant variation relative to EUD. The relative insensitivity of EUD implies that this index will be useful for dose evaluation when parameters are not known with accuracy, for the intercomparison of dose control studies and as a radiobiologically based optimization objective. However, given confidence in model parameters, the sensitivity of TCP would make it a more reliable tool for indicating potentially successful and unsuccessful irradiation strategies. It is suggested that both parameters be used in conjunction, with EUD and TCP results viewed with an appreciation of the characteristics of each model.

A Small Tolerance for Catheter Displacement in High–Dose Rate Prostate Brachytherapy is Necessary and Feasible

PURPOSE We examined catheter displacement in patients treated with fractionated high-dose rate (HDR) brachytherapy boost for prostate cancer and the impact this had on tumor control probability (TCP). These data were used to make conclusions on an acceptable amount of displacement. METHODS AND MATERIALS The last 20 patients treated with HDR brachytherapy boost for prostate cancer at our center in 2007 were replanned using simulated interstitial catheter displacements of 3, 6, 9, and 12 mm with originally planned dwell times. The computer-modeled dose-volume histograms for the clinical target volumes were exported and used to calculate the TCP of plans with displaced needles relative to the original plan. Actual catheter displacements were also measured before and after manual adjustment in all patients treated in 2007. RESULTS In the 20 patients who were replanned for caudal catheter displacements of 3, 6, 9, and 12 mm, the median relative TCP was 0.998, 0.964, 0.797, and 0.265, respectively (p < 0.01 when all medians were compared). All patients replanned with a 3-mm displacement, compared with only 75% with a 6-mm displacement, had a relative TCP greater than 0.950. In the 91 patients treated in 2007, before adjustment, 82.3% of fractions had a displacement greater than 3 mm compared with 12.2% of fractions after adjustment. CONCLUSIONS Catheter displacement in HDR brachytherapy significantly compromises the TCP. The tolerance for these movements should be small (< or =3 mm). Correcting these displacements to within acceptable limits is feasible.

Comparison of DVH data from multiple radiotherapy treatment planning systems

This study examined the variation of dose-volume histogram (DVH) data sourced from multiple radiotherapy treatment planning systems (TPSs). Treatment plan exports were obtained from 33 Australian and New Zealand centres during a dosimetry study. Plan information, including DVH data, was exported from the TPS at each centre and reviewed in a digital review system (SWAN). The review system was then used to produce an independent calculation of DVH information for each delineated structure. The relationships between DVHs extracted from each TPS and independently calculated were examined, particularly in terms of the influence of CT scan slice and pixel widths, the resolution of dose calculation grids and the TPS manufacturer. Calculation of total volume and DVH data was consistent between SWAN and each TPS, with the small discrepancies found tending to increase with decreasing structure size. This was significantly influenced by the TPS model used to derive the data. For target structures covered with relatively uniform dose distributions, there was a significant difference between the minimum dose in each TPS-exported DVH and that calculated independently.

Rectal and urinary dysfunction in the TROG 03.04 RADAR trial for locally advanced prostate cancer

BACKGROUND The RADAR trial determines whether adjuvant androgen suppression, bisphosphonates and radiation dose escalation for localised prostate cancer (PC) may improve oncologic outcomes. This study examines whether these measures increase rectal and urinary dysfunction and are secondary trial endpoints. METHODS Using a 2×2 factorial trial design men with locally advanced PC were randomly allocated 6 months i.m. leuprorelin prior to radiotherapy either alone or followed by 12 months i.m. leuprorelin. These two groups received 18 months i.v. zoledronic acid (Z) commencing at randomisation or no further treatment. Radiotherapy dose was escalated in a regulated way using external beam techniques (EBRT) or by a high dose rate brachytherapy (HDRB) boost. Prevalence rates of rectal and urinary dysfunctional symptoms were compared at baseline, the end of RT, 18 and 36 months according to treatment arm, dose and technique using multiple regression models. RESULTS Between 2003 and 2007, 1071 men were randomly allocated and eligible for inclusion in this study. No persistent differences in rectal or urinary dysfunction were attributable to treatment arm or to increasing EBRT dose. However following HDRB statistical increases (p<0.001) in urinary dysfunction were measured using the EORTC PR25 instrument at 18 and 36 months. CONCLUSION Adjuvant androgen suppression, bisphosphonates and increasing EBRT dose did not increase rectal or urinary dysfunction in this trial. However dose escalation using HDRB increased urinary dysfunction.

A Comparison of the Prognostic Value of Early PSA Test-Based Variables Following External Beam Radiotherapy, With or Without Preceding Androgen Deprivation: Analysis of Data From the TROG 96.01 Randomized Trial

PURPOSE We sought to compare the prognostic value of early prostate-specific antigen (PSA) test-based variables for the 802 eligible patients treated in the Trans-Tasman Radiation Oncology Group 96.01 randomized trial. METHODS AND MATERIALS Patients in this trial had T2b, T2c, T3, and T4 N0 prostate cancer and were randomized to 0, 3, or 6 months of neoadjuvant androgen deprivation therapy (NADT) prior to and during radiation treatment at 66 Gy to the prostate and seminal vesicles. The early PSA test-based variables evaluated were the pretreatment initial PSA (iPSA) value, PSA values at 2 and 4 months into NADT, the PSA nadir (nPSA) value after radiation in all patients, and PSA response signatures in men receiving radiation. Comparisons of endpoints were made using Cox models of local progression-free survival, distant failure-free survival, biochemical failure-free survival, and prostate cancer-specific survival. RESULTS The nPSA value was a powerful predictor of all endpoints regardless of whether NADT was given before radiation. PSA response signatures also predicted all endpoints in men treated by radiation alone. iPSA and PSA results at 2 and 4 months into NADT predicted biochemical failure-free survival but not any of the clinical endpoints. nPSA values correlated with those of iPSA, Gleason grade, and T stage and were significantly higher in men receiving radiation alone than in those receiving NADT. CONCLUSIONS The postradiation nPSA value is the strongest prognostic indicator of all early PSA-based variables. However, its use as a surrogate endpoint needs to take into account its dependence on pretreatment variables and treatment method.

a mathematical framework for separating the direct and bystander components of cellular radiation response

Abstract A mathematical model for fractional tumor cell survival was developed incorporating components of cell killing due to direct radiation interactions and bystander signals resulting from non-local dose deposition. Material and methods. Three possible mechanisms for signal production were tested by fitting predictions to available experimental results for tumor cells (non-small cell lung cancer NCI-H460 and melanoma MM576) exposed to gradient x-ray fields. The parameter fitting allowed estimation of the contribution of bystander signaling to cell death (20–50% for all models). Separation of the two components of cell killing allowed determination of the α and β parameters of the linear-quadratic model both with and without the presence of bystander signaling. Results and discussion. For both cell lines, cell death from bystander signaling and direct radiation interactions were comparable. For NCI-H460 cells, the values for α and β were 0.18 Gy−1 and 0.10 Gy−2 respectively when direct and bystander effects were combined, and 0.053 Gy−1 and 0.061 Gy−2 respectively when the signaling component was removed. For MM576, the corresponding respective values were 0.09 Gy−1 and 0.011 Gy−2 for the combined response, and 0.014 Gy−1 and 0.002 Gy−2 for the isolated direct radiation response. The bystander component in cell death was found to be significant and should not be ignored. Further experimental evidence is required to determine how these results translate to the in vivo situation where tumor control probability (TCP) models that currently assume cellular independence may need to be revised.

Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial

BACKGROUND The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. METHODS We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS±18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. RESULTS Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p<0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. CONCLUSION RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration.

Suitability of radiochromic films for dosimetry of low energy X‐rays

This study examined the response characteristics of three commercially available radiochromic films when exposed to low energy (50 kVp) X‐rays. The aim was to evaluate the films for potential use in 2D dosimetry for a low‐kV intraoperative radiotherapy (IORT) device known as the ‘Intrabeam’. Dose‐response relationships were obtained for Gafchromic EBT, XR‐RV2, and XR‐QA film in water at several distances from the Intrabeam device. It was found that the dose rates from the source were excessive for use of the XR‐QA film, and that all three film types showed significant energy dependence within the limits of measurement uncertainty. Basic modeling of primary X‐ray spectra indicated large changes in the lower energy components with distance from the source, and it is hypothesized that the changes in film response are a result of changes in film energy response. This is in contrast to previous studies indicating less or negligible energy response. All films showed non‐linearity in response over the ranges examined. These results imply significant limitations for the use of these films for low‐kV dosimetry. PACS number: 87.53.Bn

Effect of androgen deprivation therapy on muscle attenuation in men with prostate cancer

Aging skeletal muscle is associated with not only a reduction in muscle size and strength but also in muscle quality which reflects an increase in fatty infiltration of muscle. In men with prostate cancer, androgen deprivation therapy (ADT) accelerates this loss of muscle size and strength, but it is unknown if muscle quality is also adversely affected. Therefore, we examined the effects of ADT on muscle attenuation, an indirect measure of intramuscular lipid content, as well as the muscle cross‐sectional area (CSA) in men with prostate cancer.