Stan Heukelom

Differential Effects of Combined Ad5-Δ24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma

Purpose: The integrin-targeted conditionally replicating adenovirus Ad5-Δ24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-Δ24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model. Experimental Design and Results: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-Δ24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-Δ24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-Δ24RGD with 1 × 5 Gy total body irradiation or with 2 × 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-Δ24RGD. Conclusions: Combined treatment with Ad5-Δ24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.

Effect of electron contamination on scatter correction factors for photon beam dosimetry

Physical quantities for use in megavoltage photon beam dose calculations which are defined at the depth of maximum absorbed dose are sensitive to electron contamination and are difficult to measure and to calculate. Recently, formalisms have therefore been presented to assess the dose using collimator and phantom scatter correction factors, Sc and Sp, defined at a reference depth of 10 cm. The data can be obtained from measurements at that depth in a miniphantom and in a full scatter phantom. Equations are presented that show the relation between these quantities and corresponding quantities obtained from measurements at the depth of the dose maximum. It is shown that conversion of Sc and Sp determined at a 10 cm depth to quantities defined at the dose maximum such as (normalized) peak scatter factor, (normalized) tissue-air ratio, and vice versa is not possible without quantitative knowledge of the electron contamination. The difference in Sc at dmax resulting from this electron contamination compared with Sc values obtained at a depth of 10 cm in a miniphantom has been determined as a multiplication factor, Scel, for a number of photon beams of different accelerator types. It is shown that Scel may vary up to 5%. Because in the new formalisms output factors are defined at a reference depth of 10 cm, they do not require Scel data. The use of Sc and Sp values, defined at a 10 cm depth, combined with relative depth-dose data or tissue-phantom ratios is therefore recommended. For a transition period the use of the equations provided in this article and Scel data might be required, for instance, if treatment planning systems apply Sc data normalized at d(max).

On the practice of the clinical implementation of enhanced dynamic wedges.

Practical aspects of the clinical implementation of enhanced dynamic wedges (EDW) replacing manual wedges are presented and discussed extensively. A comparison between measured and calculated data is also presented. Relative dose distributions and wedge factors were calculated with a commercially available treatment planning system and measured in a water-phantom and with an ionization chamber. Wedge factor calculations and measurements were also compared with an independent method of wedge factor calculations available from the literature. Aspects of the clinical implementation, such as safety and quality assurance, were evaluated. Measurements and calculations agreed very well and were slightly better than results of previous studies. Profiles and percentage depth doses (PDDs) agreed within 1% to 1.5% and within 0.5%, respectively. Measured and calculated wedge factors ratios agreed within 0.5% to 1%. Calculated and measured EDW dose distributions showed excellent agreement, both relative and absolute. However, for safe and practical use, specific aspects need to be taken into consideration. Once the treatment planning system is commissioned properly, the clinical implementation of EDW is rather straightforward.

Dependence of the tray transmission factor on collimator setting and source-surface distance.

When blocks are placed on a tray in megavoltage x-ray beams, generally a single correction factor for the attenuation by the tray is applied for each photon beam quality. In this approach, the tray transmission factor is assumed to be independent of field size and source-surface distance (SSD). Analysis of a set of measurements performed in beams of 13 different linear accelerators demonstrates that there is, however, a slight variation of the tray transmission factor with field size and SSD. The tray factor changes about 1.5% for collimator settings varying between 4x4 cm and 40 x 40 cm for a 1 cm thick PMMA tray and approximately 3% for a 2 cm thick PMMA tray. The variation with field size is smaller if the source-surface distance is increased. The dependence on the collimator setting is not different, within the experimental uncertainty of about 0.5% (1 s.d.), for the nominal accelerating potentials and accelerator types applied in this study. It is shown that the variation of the tray transmission factor with field size and source-surface distance can easily be taken into account in the dose calculation by considering the volume of the irradiated tray material and the position of the tray in the beam. A relation is presented which can be used to calculate the numerical value of the tray transmission factor directly. These calculated values can be checked with only a few measurements using a cylindrical beam coaxial miniphantom.

Formalisms for MU calculations, ESTRO booklet 3 versus NCS report 12

Although the relevance and importance of quality assurance and quality control in radiotherapy is generally accepted, only recently, methods for monitor unit (MU) calculation and verification have been addressed in recognized recommendations, published by the European Society of Therapeutic Radiation Oncology (ESTRO) and by the Netherlands Commission on Radiation Dosimetry (Dutreix A, Bjärngard BE, Bridier A, Mijnheer B, Shaw JE, Svensson H. Monitor unit calculation for high-energy photon beams. Physics for clinical radiotherapy. ESTRO Booklet No. 3. Leuven: Garant, 1997; Netherlands Commission on Radiation Dosimetry (NCS). Determination and use of scatter correction factors of megavoltage photon beams. NCS report 12. Deift: NCS, 1998). Both documents are based on the same principles: (i) the separation of the output factor into a head and a volume (or phantom) scatter component; (ii) the use of a so-called mini-phantom to measure and verify the head scatter component; and (iii) the recommendation to use a single reference depth of 10 cm for all photon beam qualities. However, there are substantial differences between the approach developed in the IAEA-ESTRO task group and the NCS approach for MU calculations, which might lead to confusion and/or misinterpretation if both reports are used simultaneously or if data from the NCS report is applied in the algorithms of the ESTRO report without careful consideration. The aim of the present paper is to discuss and to clearly point out these differences (e.g. field size definitions, phantom scatter parameters, etc.). Additionally, corresponding quantities in the two reports are related where possible and several aspects concerning the use of a mini-phantom (e.g. size, detector position, composition) are addressed.

Comparison of parameterization methods of the collimator scatter correction factor for open rectangular fields of 6-25 MV photon beams

Abstract Purpose : To facilitate the use of the collimator scatter correction factor, S c , parametrization methods that relate S c to the field size by fitting were investigated. Materials and methods : S c was measured with a mini-phantom for five types of dual photon energy accelerators with energies varying between 6 and 25 MV. Using these S c -data six methods of parametrizing S c for square fields were compared, including a third-order polynomial of the natural logarithm of the field size normalized to the field size of 10 cm 2 . Also five methods of determining S c for rectangular fields were considered, including one which determines the equivalent field size by extending Sterlings method. Results : The deviations between measured and calculated S c -values were determined for all photon beams and methods investigated in this study. The resulting deviations of the most accurate method varied between 0.07 and 0.42% for square fields and between 0.26 and 0.79% for rectangular fields. A recommendation is given as to how to limit the number of fields for which S c should be measured in order to be able to accurately predict it for an arbitrary field size.