PURPOSE:To assess if intensity-modulated radiotherapy (IMRT) can possibly lead to improved local control and lower incidence of vision impairment/blindness in comparison to non-IMRT techniques when treating sinonasal malignancies / what is the most optimal dose constraints for the optic pathway / and the impact of different IMRT strategies on optic pathway sparing in this setting.METHODS AND MATERIALS:A literature search in the PubMed databases was conducted in July, 2012.RESULTS:Clinical studies on IMRT and 2D/3D (2 dimensional/3 dimensional) RT for sinonasal malignancies suggest improved local control and lower incidence of severe vision impairment with IMRT in comparison to non-IMRT techniques. As observed in the non-IMRT studies, blindness due to disease progression may occur despite a lack of severe toxicity possibly due to the difficulty of controlling locally very advanced disease with a dose less than or equal to] 70Gy. Concurrent chemotherapy's influence on the the risk of severe optic toxicity after radiotherapy is unclear. A maximum dose of less than or equal to] 54Gy with conventional fractionation to the optic pathway may decrease the risk of blindness. Increased magnitude of intensity modulation through increasing the number of segments, beams, and using a combination of coplanar and non-coplanar arrangements may help increase dose conformality and optic pathway sparing when IMRT is used.CONCLUSION:IMRT optimized with appropriate strategies may be the treatment of choice for the most optimal local control and optic pathway sparing when treating sinonasal malignancy.

Background: New prognostic grade groupings were recently proposed for prostate cancer. They are based on Gleason grading of either biopsy or prostatectomy specimen. Former Gleason 6 corresponds to group 1, Gleason 7=3+4 corresponds to group 2, Gleason 7=4+3 corresponds to group 3, Gleason 8 corresponds to group 4, and Gleason 9-10 correspond to group 5. Objective: To assess the prognostic value of Gleason grade groups in men with prostate cancer from a nationwide population‑based cohort. Design, Setting and Participants: From the National Prostate Cancer Register of Sweden, we identified 5,880 men diagnosed with prostate cancer from 2005 to 2007, including 4,325 who had radical prostatectomy and 1,555 treated by radiotherapy.  Outcome Measurements and Statistical Analysis: Kaplan-Meier survival analysis was used to calculate the cumulative 4-year biochemical recurrence-free survival. Cox proportional hazards regression models were used to examine the relationship between prognostic Gleason grade groups and biochemical recurrence after radical prostatectomy and radiotherapy. The 4-year biochemical progression-free survival was compared for groups based on biopsy and prostatectomy Gleason grade groups. Results and Limitations: Among men undergoing surgery, the 4‑year biochemical progression-free survival was 89%, 82%, 74%, 77%, and 49% for prognostic Gleason grade groups 1-5 on biopsy. The corresponding 4-year biochemical progression-free survival based on prostatectomy prognostic Gleason grade groups was 92%, 85%, 73%, 63%, and 51% for prognostic Gleason grade groups 1-5. For men undergoing radiotherapy, biopsy prognostic Gleason grade groups 1-5 had 4-year biochemical progression-free survival of 95%, 91%, 85%, 78%, and 70%. After adjusting for preoperative serum prostate specific antigen and clinical stage, biopsy prognostic Gleason grade groups were significant independent predictors of biochemical progression after radical prostatectomy and radiotherapy. There was no central review of pathology. Conclusions: These results confirm the prognostic value of the newly proposed prognostic Gleason grade groups in men undergoing radical prostatectomy and radiotherapy in a population-based setting.

Image guidance has rapidly become central to current radiotherapy practice. A uniform framework is developed for evaluating image quality across all imaging modalities by modelling the ‘universal phantom’: breaking any phantom down into its constituent fundamental test objects and applying appropriate analysis techniques to these through the construction of an automated analysis tree. This is implemented practically through the new software package ‘IQWorks’ and is applicable to both radiotherapy and diagnostic imaging. For electronic portal imaging (EPI), excellent agreement was observed with two commercial solutions: the QC-3V phantom and PIPS Pro software (Standard Imaging) and EPID QC phantom and epidSoft software (PTW). However, PIPS Pro’s noise correction strategy appears unnecessary for all but the highest frequency modulation transfer function (MTF) point and its contrast to noise ratio (CNR) calculation is not as described. Serious flaws identified in epid- Soft included erroneous file handling leading to incorrect MTF and signal to noise ratio (SNR) results, and a sensitivity to phantom alignment resulting in overestimation of MTF points by up to 150% for alignment errors of only ±1 pixel. The ‘QEPI1’ is introduced as a new EPI performance phantom. Being a simple lead square with a central square hole it is inexpensive and straightforward to manufacture yet enables calculation of a wide range of performance metrics at multiple locations across the field of view. Measured MTF curves agree with those of traditional bar pattern phantoms to within the limits of experimental uncertainty. An intercomparison of the Varian aS1000 and aS500-II detectors demonstrated an improvement in MTF for the aS1000 of 50–100% over the clinically relevant range 0.4–1 cycles/mm, yet with a corresponding reduction in CNR by a factor of p 2. Both detectors therefore offer advantages for different clinical applications. Characterisation of cone-beam CT (CBCT) facilities on two Varian On-Board Imaging (OBI) units revealed that only two out of six clinical modes had been calibrated by default, leading to errors of the order of 400 HU for some modes and materials – well outside the ±40 HU tolerance. Following calibration, all curves agreed sufficiently for dose calculation accuracy within 2%. CNR and MTF experiments demonstrated that a boost in MTF f50 of 20–30% is achievable by using a 5122 rather than a 3842 matrix, but with a reduction in CNR of the order of 30%. The MTF f50 of the single-pulse half-resolution radiographic mode of the Varian PaxScan 4030CB detector was measured in the plane of the detector as 1.0±0.1 cycles/mm using both a traditional tungsten edge and the new QEPI1 phantom. For digitally reconstructed radiographs (DRRs), a reduction in CT slice thickness resulted in an expected improvement in MTF in the patient scanning direction but a deterioration in the orthogonal direction, with the optimum slice thickness being 1–2 mm. Two general purposes display devices were calibrated against the DICOM Greyscale Standard Display Function (GSDF) to within the ±20% limit for Class 2 review devices. By providing an approach to image quality evaluation that is uniform across all radiotherapy imaging modalities this work enables consistent end-to-end optimisation of this fundamental part of the radiotherapy process, thereby supporting enhanced use of image-guidance at all relevant stages of radiotherapy and better supporting the clinical decisions based on it.

<p>Funding Agency:</p><p>Health Research Council in the South-East of Sweden</p>

A genetically determined high level of intrinsic normal tissue radiosensitivity may account for the 5% of patients who experience unexpectedly severe normal tissue side effects following radiotherapy. The pre-treatment identification of these individuals by a diagnostic test or “predictive assay “ may allow appropriate modification of treatment plans and improve the therapeutic index of radiotherapy. Results from studies of cell-based assays measuring the response of a single cell type taken from patients to in vitro irradiation have been inconsistent, leading to the opinion of many that they are of no value in the prediction of normal tissue radiosensitivity. A systematic review of the literature presented here, however, suggests that poor methodology of study design often with inadequate control for those factors other than normal tissue radiosensitivity which influence radiotherapy toxicity and lack of reporting of assay precision means that it is difficult to form any conclusions, positive or negative about the diagnostic accuracy of the cell-based assays studied so far. Analysis of individual patient data extracted from these studies suggests that at least some of these assays may possess some discriminatory value. This finding justified an attempt to develop a novel cell-based assay based on the kinetics of radiation-induced .H2AX in peripheral blood lymphocytes. Assay failure rate was high and intra- and inter-sample assay reproducibility was poor for quantification by microscopy but were better for flow cytometric analysis. A study of 8 volunteers, however, demonstrated that intra-individual variation was higher than inter-individual variation in assay results, strongly suggesting that poor assay reproducibility due to technical or biological factors may limit the assay’s potential to identify radiosensitive individuals. This suspicion needs to be confirmed in a clinical study of patients of known radiosensitivity. As blood sample storage conditions affect assay results these will need to be standardized to prevent confounding of results.

published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

published_or_final_version / Dentistry / Doctoral / Doctor of Philosophy

In recent years, the impressive progress performed in imaging, computational and technological fields have made possible the emergence of image-guided radiation therapy (IGRT) and adaptive radiation therapy (ART). The accuracy in radiation dose delivery reached by IMRT offers the possibility to increase locoregional dose-intensity, potentially overcoming the poor tumor control achieved by standard approaches. However, before implementing such a technique in clinical routine, a particular attention has to be paid at the target volumes definition and delineation procedures to avoid inadequate dosage to TVs/OARs. In head and neck squamous cell carcinoma (HNSCC), the GTV is typically defined on CT acquired prior to treatment. However, providing functional information about the tumor, FDG-PET might advantageously complete the classical CT-Scan to better define the TVs. Similarly, re-imaging the tumor with optimal imaging modality might account for the constantly changing anatomy and tumor shape occurring during the course of fractionated radiotherapy. Integrating this information into the treatment planning might ultimately lead to a much tighter dose distribution. From a methodological point of view, the delineation of TVs on anatomical or functional images is not a trivial task. Firstly, the poor soft tissue contrast provided by CT comes out of large interobserver variability in GTV delineation. In this regard, we showed that the use of consistent delineation guidelines significantly improved consistency between observers, either with CT and with MRI. Secondly, the intrinsic characteristics of PET images, including the blur effect and the high level of noise, make the detection of the tumor edges arduous. In this context, we developed specific image restoration tools, i.e. edge-preserving filters for denoising, and deconvolution algorithms for deblurring. This procedure restores the image quality, allowing the use of gradient-based segmentation techniques. This method was validated on phantom and patient images, and proved to be more accurate and reliable than threshold-based methods. Using these segmentation methods, we proved that GTVs significantly shrunk during radiotherapy in patients with HNSCC, whatever the imaging modality used (MRI, CT, FDG-PET). No clinically significant difference was found between CT and MRI, while FDG-PET provided significantly smaller volumes than those based on anatomical imaging. Refining the target volume delineation by means of functional and sequential imaging ultimately led to more optimal dose distribution to TVs with subsequent soft tissue sparing. In conclusion, we demonstrated that a multi-modality-based adaptive planning is feasible in HN tumors and potentially opens new avenues for dose escalation strategies. As a high level of accuracy is required by such approach, the delineation of TVs however requires a special care.