Longitudinal evaluation of the metabolic response of a tumor xenograft model to single fraction radiation therapy using magnetic resonance spectroscopy.

Proton magnetic resonance spectroscopy (MRS) was used to evaluate the metabolic profile of human glioblastoma multiform brain tumors grown as xenografts in nude mice before, and at multiple time points after single fraction radiation therapy. Tumors were grown over the thigh in 16 mice in this study, of which 5 served as untreated controls and 11 had their tumors treated to 800 cGy with 200 kVp x-rays. Spectra were acquired within 24 h pre-treatment, and then at 3, 7 and 14 d post-treatment using a 9.4 T animal magnetic resonance (MR) system. For the untreated control tumors, spectra (1-2 per mouse) were acquired at different stages of tumor growth. Spectra were obtained with the PRESS pulse sequence using a 3  ×  3 × 3 mm(3) voxel. Analysis was performed with the LCModel software platform. Six metabolites were profiled for this analysis: alanine (Ala), myo-inositol (Ins), taurine (Tau), creatine and phosphocreatine (Cr + PCr), glutamine and glutamate (Glu + Gln), and total choline (glycerophosphocholine + phosphocholine) (GPC + PCh). For the treated cohort, most metabolite/water concentration ratios were found to decrease in the short term at 3 and 7 d post-treatment, followed by an increase at 14 d post-treatment toward pre-treatment values. The lowest concentrations were observed at 7 d post-treatment, with magnitudes (relative to pre-treatment concentration ratios) of: 0.42  ±  24.6% (Ala), 0.43  ±  15.3% (Ins), 0.68  ±  27.9% (Tau), 0.52  ±  14.6% (GPC+PCh), 0.49  ±  21.0% (Cr + PCr) and 0.78  ±  24.5% (Glu + Gln). Control animals did not demonstrate any significant correlation between tumor volume and metabolite concentration, indicating that the observed kinetics were the result of the therapeutic intervention. We have demonstrated the feasibility of using MRS to follow multiple metabolic markers over time for the purpose of evaluating therapeutic response of tumors to radiation therapy. This study provides supporting evidence that metabolite/water concentration ratios have the potential to be used as biomarkers for the assessment of the response to therapy.

A pan-Canadian practice guideline and algorithm: screening, assessment, and supportive care of adults with cancer-related fatigue.

PURPOSE: The purpose of the present systematic review was to develop a practice guideline to inform health care providers about screening, assessment, and effective management of cancer-related fatigue (crf) in adults. METHODS: The internationally endorsed adapte methodology was used to develop a practice guideline for pan-Canadian use. A systematic search of the literature identified a broad range of evidence: clinical practice guidelines, systematic reviews, and other guidance documents on the screening, assessment, and management of crf. The search included medline, embase, cinahl, the Cochrane Library, and other guideline and data sources to December 2009. RESULTS: Two clinical practice guidelines were identified for adaptation. Seven guidance documents and four systematic reviews also provided supplementary evidence to inform guideline recommendations. Health professionals across Canada provided expert feedback on the adapted recommendations in the practice guideline and algorithm through a participatory external review process. CONCLUSIONS: Practice guidelines can facilitate the adoption of evidence-based assessment and interventions for adult cancer patients experiencing fatigue. Development of an algorithm to guide decision-making in practice may also foster the uptake of a guideline into routine care.

Sci-Fri PM: Delivery - 09: Response of a tumor xenograft model to radiation therapy using magnetic resonance spectroscopy.

9.4T 1 H magnetic resonance spectroscopy (MRS) was utilized to track the response of mouse xenograft glioblastoma multiform (GBM) brain tumors to single fraction radiation therapy. Six metabolites were analyzed with LCModel: alanine (Ala), myo-inositol (Ins), taurine (Tau), creatine and phosphocreatine (Cr + PCr), glutamine and glutamate (Glu + Gln), and total choline (glycerophosphocholine + phosphocholine) (GPC + PCh). 11 mice received 800 cGy of 200 kVp x-rays, 5 were untreated controls. PRESS spectra (27 µL volumes) were acquired at multiple time points for treated and control animals. In treated animals, all metabolite : water ratios decreased 3 days post-treatment, with further decreases at day 7, and then increases at day 14 relative to the 7 day mark. Concentrations on day 7 relative to pre-treatment were as follows: 0.42 (Ala), 0.43 (Ins), 0.68 (Tau), 0.52 (GPC+PCh), 0.49 (Cr + PCr) and 0.78 (Glu + Gln). Metabolite ratios did not correlate with tumor volume in control animals, suggesting a real therapeutic response was observed. Our 1 H MRS data suggests that perturbations in the metabolic signature of GBM cancers occur in response to irradiation. Such changes in the metabolite : water concentration ratios could potentially be exploited for the improvement of radiotherapy.

Poster - Thur Eve - 49: Application of plastic scintillating detectors to orthovoltage x-ray measurements.

Plastic scintillating detectors (PSDs) have found numerous dosimetric applications in radiotherapy due to their approximate water equivalence at high energies and their small physical size. At low photon energies, however, the ratio of mass attenuation coefficients (PSD : water) deviates from unity, which potentially limits their utility in this range. In this work, measurements of orthovoltage cutout factors were made with PSDs and and ion chamber. Results were compared to Monte Carlo simulations of the same geometry. Results indicated that the PSDs performed better than the IC in almost all field sizes. Further work is required to more thoroughly characterize the Monte Carlo model of the x-ray unit and to investigate any discrepancies that might have resulted from slight differences in the effective point of measurement of the two detector systems.

Feeding ecology of King George whiting Sillaginodes punctatus (Perciformes) recruits in seagrass and unvegetated habitats. Does diet reflect habitat utilization?

This study investigated the feeding ecology of King George whiting Sillaginodes punctatus recruits to determine how diet composition varies between habitat types (seagrass and unvegetated habitats), and between sites separated by distance. Broad-scale sampling of seagrass and unvegetated habitats at nine sites in Port Phillip Bay (Australia) indicated the diet composition varied more by distance into the bay than by habitat. Near the entrance to the bay the diet was dominated by harpacticoids and gammarid amphipods, in the middle reaches of the bay the diet was completely dominated by harpacticoids, while at sites furthest into the bay, mysids and crab zoea were also important. Abundances of prey in guts was significantly higher between 1000 and 2200 hours compared with other times, indicating diurnal feeding. Laboratory determined gut evacuation rate (based on an exponential model) was estimated to be -0·54. Daily rations were highly variable among sites and habitat types. Sillaginodes punctatus recruits consumed much higher quantities of prey on unvegetated habitat than seagrass habitat at some middle reach sites; with prey consumption of harpacticoid copepods on unvegetated habitat approaching 3000 individuals per day at one site. The results of this study provide insight into why habitat associations of S. punctatus recruits within mosaics of seagrass and unvegetated habitat show high spatial variation.

Relative biological damage and electron fluence in and out of a 6 MV photon field.

Scattered radiation in the penumbra of a megavoltage radiation therapy beam can deposit a non-negligible dose in the healthy tissue around a target volume. The lower energy of the radiation in this region suggests that its biological effectiveness might not be the same as that of the open beam. In this work, we determined the relative biological damage in normal human fibroblasts after megavoltage irradiation in two geometries. The first was an open-beam irradiation and the second was a blocked configuration in which only scattered radiation could reach the target cells. The biological damage was evaluated by the gamma-H2AX immunofluorescence assay, which is capable of detecting DNA double-strand breaks in individual cells. We report that the scattered radiation is more effective at producing biological damage than the open beam radiation. We found a 27% enhancement in the net mean nuclear gamma-H2AX fluorescence intensity at 2 Gy and a 48% enhancement at 4 Gy. These findings are of interest due to the increased doses of penumbral radiation close to target volumes both in dose escalation studies and in IMRT treatment deliveries where high dose gradients exist for the purpose of conformal avoidance of healthy tissues.

Sci-Sat AM(1): Imaging-01: Tumour and normal tissue T2 and ADC distributions for a mouse model at 9.4T.

Magnetic resonance (MR) measurements of relaxation times and diffusion coefficient in tissue have been demonstrated to be sensitive to biological changes induced by radiation therapy. We are currently using mouse models of human glioblastoma multiforme (GBM) to study tumour response to ionizing radiation by MRI at 9.4T. Utilizing conventional imaging techniques coupled with quantitative measurements of transverse relaxation time (T2) and apparent diffusion coefficient (ADC), we monitor changes during tumour growth and subsequent changes after single-fraction radiotherapy. In addition to tumour parameters, we have measured T2 and ADC in other structures that appear in the same transverse slices as tumour tissue. Here we report the measured distributions of T2 and ADC in tumour and in normal tissues that are likely to be encountered during MR imaging of tumour xenografts in mice, including liver, kidney, fat, skeletal muscle, spinal cord, and brain. Quantitative knowledge of these distributions in normal tissue is important in optimizing the sequences used for imaging of these tissues, and in optimizing continued measurements of T2 and ADC changes. Knowledge of parameter distributions in tumour is important because recent studies have suggested that the T2 and ADC responses after therapy may be the result of large shifts in smaller isolated pockets of tumour, rather than more moderate shifts in T2 and ADC over the whole tumour volume. These distributions provide a baseline measurement of typical distributions in advance of radiation therapy.

A Monte Carlo study of the variation of electron fluence in water from a 6 MV photon beam outside of the field.

Existing studies have suggested some debate on whether the quality of radiation that delivers dose outside of the primary field of a radiotherapy photon beam can be considered the same as that inside the primary field. We used a Monte Carlo approach to simulate the electron fluence differential in energy inside a water phantom in response to irradiation by a 6 MV photon beam. The goal was to quantify how significantly the electron fluence changes when moving from a volume exposed to the primary field to one outside of the primary field, and understand any potential biological implications. We scored the electron fluence outwards in annular volumes in response to a 5 cm radius 6 MV beam and at the central axis in response to a rectangular 6 MV beam partially blocked by an MLC. The resulting fluence spectra were compared to different low-LET sources for which biological response in the form of chromosomal aberrations has been published. Our results show a significant increase in the low energy component of the fluence spectra outside of the primary field, which increases the mean LET to values similar to that seen in response to a 137Cs photon source. In turn, it is shown that this has the potential to increase the RBE.

3D interfractional patient position verification using 2D-3D registration of orthogonal images.

Reproducible positioning of the patient during fractionated external beam radiation therapy is imperative to ensure that the delivered dose distribution matches the planned one. In this paper, we expand on a 2D-3D image registration method to verify a patient's setup in three dimensions (rotations and translations) using orthogonal portal images and megavoltage digitally reconstructed radiographs (MDRRs) derived from CT data. The accuracy of 2D-3D registration was improved by employing additional image preprocessing steps and a parabolic fit to interpolate the parameter space of the cost function utilized for registration. Using a humanoid phantom, precision for registration of three-dimensional translations was found to be better than 0.5 mm (1 s.d.) for any axis when no rotations were present. Three-dimensional rotations about any axis were registered with a precision of better than 0.2 degrees (1 s.d.) when no translations were present. Combined rotations and translations of up to 4 degrees and 15 mm were registered with 0.4 degrees and 0.7 mm accuracy for each axis. The influence of setup translations on registration of rotations and vice versa was also investigated and mostly agrees with a simple geometric model. Additionally, the dependence of registration accuracy on three cost functions, angular spacing between MDRRs, pixel size, and field-of-view, was examined. Best results were achieved by mutual information using 0.5 degrees angular spacing and a 10 x 10 cm2 field-of-view with 140 x 140 pixels. Approximating patient motion as rigid transformation, the registration method is applied to two treatment plans and the patients' setup errors are determined. Their magnitude was found to be < or = 6.1 mm and < or = 2.7 degrees for any axis in all of the six fractions measured for each treatment plan.

Patient specific treatment verifications for helical tomotherapy treatment plans.

We performed two-dimensional treatment verifications for ten patients planned and treated with helical tomotherapy. The treatment verification consisted of a film measurement as well as point dose measurements made with an ion chamber. The agreement between the calculated and the measured film dose distributions was evaluated with the gamma index calculated for three sets of criteria (2 mm and 2%, 4 mm and 3%, and 3 mm and 5%) as recommended in the literature. Good agreement was found between measured and calculated distributions without any need of normalization of the dose data but with dose map registration using reference marks. In this case, 69.8 +/- 17.2%, 92.6 +/- 9.0%, and 93.4 +/- 8.5% passed the 2 mm and 2%, 4 mm and 3%, and 3 mm and 5% criteria, respectively. Agreement was excellent when both normalization and manual registration of the dose maps was employed. In this case 91.2 +/- 5.6%, 99.0 +/- 1.4%, and 99.5 +/- 0.8% passed the 2 mm and 2%, 4 mm and 3%, and 3 mm and 5% criteria, respectively. The mean percent discrepancy for the point dose measurements was -0.5 +/- 1.1%, -2.4 +/- 3.7%, -1.1 +/- 7.3% for the high dose, low dose, and critical structure point, respectively. Three criteria for a satisfactory treatment verification in the high dose regions of a plan were established. For the un-normalized reference mark registered data 80% of pixels must pass the 3 mm and 5% criteria. For the normalized and manually registered data, 80% must pass the 2 mm and 2% criteria, and the point dose measurement must be within 2% of the calculated dose. All low dose region/critical structure point dose measurements were evaluated on a patient by patient basis. The criteria we recommend can be useful for the routine evaluation of treatment plans for tomotherapy systems.

Monte Carlo investigation of single cell beta dosimetry for intraperitoneal radionuclide therapy.

Single event spectra for five beta-emitting radionuclides (Lu-177, Cu-67, Re-186, Re-188, Y-90) were calculated for single cells from two source geometries. The first was a surface-bound isotropically emitting point source and the second was a bath of free radioactivity in which the cell was submerged. Together these represent a targeted intraperitoneal radionuclide therapy. Monoenergetic single event spectra were calculated over an energy range of 11 keV to 2500 keV using the EGSnrc Monte Carlo system. Radionuclide single event spectra were constructed by weighting monoenergetic single event spectra according to radionuclide spectra appropriate for each source geometry. In the case of surface-bound radioactivity, these were radionuclide beta decay spectra. For the free radioactivity, a continuous slowing down approximation spectrum was used that was calculated based on the radionuclide decay spectra. The frequency mean specific energy per event increased as the energy of the beta emitter decreased. This is because, at these energies, the stopping power of the electrons decreases with increasing energy. The free radioactivity produced a higher frequency mean specific energy per event than the corresponding surface-bound value. This was primarily due to the longer mean path length through the target for this geometry. This information differentiates the radionuclides in terms of the physical process of energy deposition and could be of use in the radionuclide selection procedure for this type of therapy.

Dosimetric model for intraperitoneal targeted liposomal radioimmunotherapy of ovarian cancer micrometastases.

A simple model has been developed to investigate the dosimetry of micrometastases in the peritoneal cavity during intraperitoneal targeted liposomal radioimmunotherapy. The model is applied to free-floating tumours with radii between 0.005 cm and 0.1 cm. Tumour dose is assumed to come from two sources: free liposomes in solution in the peritoneal cavity and liposomes bound to the surface of the micrometastases. It is assumed that liposomes do not penetrate beyond the surface of the tumours and that the total amount of surface antigen does not change over the course of treatment. Integrated tumour doses are expressed as a function of biological parameters that describe the rates at which liposomes bind to and unbind from the tumour surface, the rate at which liposomes escape from the peritoneal cavity and the tumour surface antigen density. Integrated doses are translated into time-dependent tumour control probabilities (TCPs). The results of the work are illustrated in the context of a therapy in which liposomes labelled with Re-188 are targeted at ovarian cancer cells that express the surface antigen CA-125. The time required to produce a TCP of 95% is used to investigate the importance of the various parameters. The relative contributions of surface-bound radioactivity and unbound radioactivity are used to assess the conditions required for a targeted approach to provide an improvement over a non-targeted approach during intraperitoneal radiation therapy. Using Re-188 as the radionuclide, the model suggests that, for microscopic tumours, the relative importance of the surface-bound radioactivity increases with tumour size. This is evidenced by the requirement for larger antigen densities on smaller tumours to affect an improvement in the time required to produce a TCP of 95%. This is because for the smallest tumours considered, the unbound radioactivity is often capable of exerting a tumouricidal effect before the targeting agent has time to accumulate significantly on the tumour surface.